TWI752580B - Kras mutant protein inhibitor - Google Patents

Kras mutant protein inhibitor Download PDF

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TWI752580B
TWI752580B TW109126693A TW109126693A TWI752580B TW I752580 B TWI752580 B TW I752580B TW 109126693 A TW109126693 A TW 109126693A TW 109126693 A TW109126693 A TW 109126693A TW I752580 B TWI752580 B TW I752580B
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pyrimidin
tetrahydropyrido
acetonitrile
piperazin
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TW202115065A (en
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高攀亮
馬存波
王鵬
劉丹
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大陸商北京加科思新藥研發有限公司
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Abstract

The present invention relates to KRAS mutant protein inhibitors. The structural formula of the KRAS mutant protein inhibitor is as shown in formula (I), and the definition of each substituent in formula (I) is as described in the specification. In addition, the present invention also relates to a composition containing the inhibitor and use thereof. The compound of the present invention has good activity of inhibiting tumor growth, and has good safety.

Description

KRAS突變蛋白抑制劑KRAS mutein inhibitor

本發明涉及式（I）所示的KRAS突變蛋白抑制劑、含有該抑制劑的組合物及其用途。The present invention relates to a KRAS mutein inhibitor represented by formula (I), a composition containing the inhibitor, and use thereof.

RAS代表一組189個胺基酸的單體球狀蛋白質(21kDa分子量)，其與質膜密切相關的，並且其結合GDP或GTP任一者。RAS起著分子開關的作用。當RAS含有結合的GDP時，其處於休眠或關閉位置並且是「無活性的」。當細胞暴露於某些促進生長的刺激物時，RAS被誘導將其結合的GDP交換為GTP。在結合GTP的情形下，RAS被「開啟」，並且能夠與其它蛋白質(其「下游靶標」)相互作用並將它們激活。RAS蛋白本身將GTP水解回到GDP從而使其自身變成關閉狀態的固有能力非常低。關閉RAS需要被稱作GTP酶激活蛋白(GAP)的外源蛋白，其與RAS相互作用，並大大地加快GTP向GDP的轉化。RAS中影響其與GAP相互作用或將GTP轉化回到GDP的能力的任何突變都將導致蛋白質的長時間激活，並因此向細胞發出信號，告訴其繼續生長和分裂。因為這些信號導致細胞生長和分裂，所以過度活躍的RAS信號傳導可能最終會導致癌症。RAS represents a group of 189 amino acid monomeric globular proteins (21 kDa molecular weight) that are closely associated with the plasma membrane and which bind either GDP or GTP. RAS acts as a molecular switch. When RAS contains bound GDP, it is in a dormant or closed position and is "inactive". When cells are exposed to certain growth-promoting stimuli, RAS is induced to exchange its bound GDP for GTP. In the context of binding GTP, RAS is "turned on" and is able to interact with other proteins (its "downstream targets") and activate them. The inherent ability of the RAS protein itself to hydrolyze GTP back to GDP thereby turning itself into the off state is very low. Shutting down RAS requires an exogenous protein called GTPase activating protein (GAP), which interacts with RAS and greatly accelerates the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in prolonged activation of the protein and thus signal the cell to continue growing and dividing. Because these signals cause cells to grow and divide, overactive RAS signaling may ultimately lead to cancer.

在結構上，RAS蛋白含有G結構域，所述結構域負責RAS的酶促活性-鳥嘌呤核苷酸結合及水解(GTP酶反應)。其還含有被稱為CAAX盒的C末端延伸區，所述延伸區可以被翻譯後修飾，並且負責將蛋白質靶向細胞膜。G結構域大小為約21-25kDa，並且其含有磷酸結合環(P環)。P環代表核苷酸在蛋白質中結合的袋，並且這是具有保守胺基酸殘基的結構域的剛性部分，所述保守胺基酸殘基是核苷酸結合及水解所必需的(甘胺酸12、蘇胺酸26和賴胺酸16)。G結構域還含有所謂的開關I(殘基30-40)和開關II(殘基60-76)區，這兩者都是蛋白質的動態部分，其常常被表示為「彈簧加載」機制，這是因為它們能夠在休眠與加載狀態之間切換。關鍵的相互作用是由蘇胺酸-35和甘胺酸-60與GTP的γ-磷酸酯形成的氫鍵，它們分別維持開關1區和開關2區處於其活性構象。在GTP水解和磷酸酯釋放後，這兩者鬆弛成非活性GDP構象。Structurally, RAS proteins contain a G domain, which is responsible for the enzymatic activity of RAS - guanine nucleotide binding and hydrolysis (GTPase reaction). It also contains a C-terminal extension called the CAAX box, which can be post-translationally modified and is responsible for targeting proteins to the cell membrane. The G domain is about 21-25 kDa in size, and it contains a phosphate-binding loop (P-loop). The P-loop represents the pocket in which nucleotides bind in proteins, and this is a rigid part of a domain with conserved amino acid residues necessary for nucleotide binding and hydrolysis (glycan amino acid 12, threonine 26 and lysine 16). The G domain also contains the so-called switch I (residues 30-40) and switch II (residues 60-76) regions, both of which are dynamic parts of the protein that are often expressed as a "spring-loaded" mechanism, which Because they can switch between sleeping and loading states. The key interactions are the hydrogen bonds formed by threonine-35 and glycine-60 with the γ-phosphate of GTP, which maintain the switch 1 and switch 2 domains, respectively, in their active conformations. After GTP hydrolysis and phosphate release, both relax to the inactive GDP conformation.

RAS亞家族中最著名的成員是HRAS、KRAS和NRAS，主要是因為它們與許多類型的癌症有牽連。RAS基因的三種主要亞型(HRAS、NRAS或KRAS)中的任一者的突變都是人類腫瘤發生中最常見的事件。發現所有人類腫瘤中有約30％在RAS基因中攜帶一些突變。值得注意的是，在25-30％的腫瘤中檢測到KRAS突變。相比之下，在NRAS和HRAS家族成員中致癌突變的發生率要低得多(分別為8％和3％)。最常見的KRAS突變見於P環中的殘基G12和G13處以及殘基Q61處。The best known members of the RAS subfamily are HRAS, KRAS, and NRAS, mainly because of their implication in many types of cancer. Mutations in any of the three major subtypes of the RAS gene (HRAS, NRAS or KRAS) are the most common events in human tumorigenesis. About 30% of all human tumors were found to carry some mutation in the RAS gene. Notably, KRAS mutations are detected in 25-30% of tumors. In contrast, the incidence of oncogenic mutations was much lower in NRAS and HRAS family members (8% and 3%, respectively). The most common KRAS mutations are found in the P-loop at residues G12 and G13 and at residue Q61.

G12C是KRAS基因的頻繁突變(甘胺酸-12突變為半胱胺酸)。已經在約13％的癌症發生、約43％的肺癌發生以及在幾乎100％的MYH相關息肉病(家族性結腸癌綜合征)中發現了這種突變。然而，用小分子靶向該基因具有挑戰性。G12C is a frequent mutation of the KRAS gene (glycine-12 to cysteine). This mutation has been found in about 13% of cancers, about 43% of lung cancers, and in almost 100% of MYH-associated polyposis (familial colon cancer syndrome). However, targeting this gene with small molecules is challenging.

因此，儘管在此領域中已取得進展，但本領域中仍然需要用於例如通過抑制KRAS、HRAS或NRAS來治療癌症的改進的化合物及方法。本發明滿足此需求並提供進一步的相關優點。Therefore, despite the progress made in this field, there remains a need in the art for improved compounds and methods for treating cancer, eg, by inhibiting KRAS, HRAS or NRAS. The present invention satisfies this need and provides further related advantages.

一方面，提供式（I）的化合物、其藥學上可接受的鹽或其立體異構體:

Figure 02_image007
(I) 其中， 每個L1 在每次出現時獨立地選自不存在、(CR5 R6 )m 、C(=O)、O、NR8 、S、S(=O)或S(=O)2 ； 每個R1 在每次出現時獨立地選自氫、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-C6-10 芳基、-C1-6 亞烷基-C6-10 芳基、5-10元雜芳基、-C1-6 亞烷基-(5-10元雜芳基)、3-10元雜環基、-C1-6 亞烷基-(3-10元雜環基)、-C3-10 碳環基或-C1-6 亞烷基-C3-10 碳環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、S、S=O或S(=O)2 的雜原子；每個R1 在每次出現時獨立地可選地被1、2、3、4、5或6個R11 取代或被1、2、3、4、5或6個R12 取代或不被取代； 每個R11 在每次出現時獨立地選自-C6-10 芳基、-C1-6 亞烷基-C6-10 芳基、5-10元雜芳基、-C1-6 亞烷基-(5-10元雜芳基)、3-10元雜環基、-C1-6 亞烷基-(3-10元雜環基)、-C3-10 碳環基或-C1-6 亞烷基-C3-10 碳環基；每個R11 獨立地可選地被1、2、3、4、5或6個R12 取代或不被取代； 每個R12 在每次出現時獨立地選自鹵素、氧代、-C1-6 烷基、-C1-6 亞烷基-(鹵素)1-3 、C1-6 雜烷基、-CN、-OR8 、-C1-6 亞烷基-(OR8 )1-3 、-O-C1-6 亞烷基-(鹵素)1-3 、-SR8 、-S-C1-6 亞烷基-(鹵素)1-3 、-NR8 R9 、-C1-6 亞烷基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 或-C3-6 碳環基；每個R12 獨立地可選地被1、2、3、4、5或6個選自鹵素、-C1-6 烷基、-C1-6 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R2 在每次出現時獨立地選自鹵素、氧代、-C1-6 烷基、-C1-6 亞烷基-(鹵素)1-3 、C1-6 雜烷基、-CN、-OR8 、-C1-6 亞烷基-(OR8 )1-3 、-NR8 R9 、-C1-6 亞烷基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 、或-C3-6 碳環基；每個R2 獨立地可選地被1、2、3、4、5或6個選自鹵素、-C1-6 烷基、-C1-6 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 的取代基取代或不取代； 每個L3 在每次出現時獨立地選自不存在、(CR5 R6 )m 、C(=O)、O、NR8 、S、S(=O)或S(=O)2 ； 每個環A是C3-10 碳環，所述的
Figure 02_image010
和
Figure 02_image012
可以連接在所述環A的相同的碳原子上或不同的原子上； 每個R3 是-OR8 、-NR8 R9 、-SR8 、-S(=O)R8 、-S(=O)2 R8 、5-10元雜芳基或3-10元雜環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、S、S=O或S(=O)2 的雜原子，每個R3 在每次出現時獨立地可選地被1、2、3、4、5或6個R10 取代或不取代； 每個L4 在每次出現時獨立地選自不存在、(CR5 R6 )m 、C(=O)、O、NR8 、S、S(=O)或S(=O)2 ； 每個R4 在每次出現時獨立地選自
Figure 02_image014
、
Figure 02_image016
、
Figure 02_image018
或
Figure 02_image020
、每個R4 在每次出現時獨立地可選地被1、2、3、4、5或6個R42 取代或不取代； 每個G1 、G2 、G3 和G4 在每次出現時獨立地選自N或CR5 ； 每個n1、n2、n3、n4、n5在每次出現時獨立地選自0、1、2、3、4、5或6，條件是n1和n2不同時為0，n3和n4不同時為0； 每個R41 在每次出現時獨立地選自
Figure 02_image022
； 每個Q在每次出現時獨立地選自C(=O)、NR8 C(=O)、S(=O)2 或NR8 S(=O)2 ；
Figure 02_image024
選自
Figure 02_image026
或
Figure 02_image028
； 當
Figure 02_image024
選自
Figure 02_image026
時，每個R4a 、R4b 和R4c 在每次出現時獨立地選自氫、鹵素、氧代、-C1-6 烷基、-C1-6 亞烷基-(鹵素)1-3 、C1-6 雜烷基、-CN、-OR8 、-C1-6 亞烷基-(OR8 )1-3 、-NR8 R9 、-C1-6 亞烷基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-C1-6 亞烷基-C(=O)NR8 R9 、-NR8 C(=O)R8 、-C1-6 亞烷基-NR8 C(=O)R8 、-S(O)2 NR8 R9 或-C3-10 碳環基；每個R4a 、R4b 和R4c 獨立地可選地被1、2、3、4、5或6個選自鹵素、-C1-6 烷基、-C1-6 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 的取代基取代或不取代；或R4b 和R4c 與它們共同連接的碳原子形成選自C3-10 碳環或3-10元雜環，每個雜環在每次出現時包含1、2或3個選自N、O、S、SO或S(O)2 的雜原子，且每個碳環基或雜環可以被1、2、3、4、5或6個選自鹵素、-C1-6 烷基、-C1-6 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 ,或-S(O)2 NR8 R9 的取代基取代或不取代；或 當
Figure 02_image024
選自
Figure 02_image028
時，每個R4a 是不存在，且R4b 和R4c 中的一個選自不存在，R4b 和R4c 中的另一個選自氫、鹵素、氧代、-C1-6 烷基、-C1-6 亞烷基-(鹵素)1-3 、C1-6 雜烷基、-CN、-OR8 、-C1-6 亞烷基-(OR8 )1-3 、-NR8 R9 、-C1-6 亞烷基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-C1-6 亞烷基-C(=O)NR8 R9 、-NR8 C(=O)R8 、-C1-6 亞烷基-NR8 C(=O)R8 、-S(O)2 NR8 R9 或-C3-10 碳環基；每個R4b 或R4c 獨立地可選地被1、2、3、4、5或6個選自鹵素、-C1-6 烷基、-C1-6 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R42 選自鹵素、氧代、-C1-6 烷基、-C1-6 亞烷基-(鹵素)1-3 、C1-6 雜烷基、-C2-6 烯基、-C2-6 炔基、-OR8 、-C1-6 亞烷基-(OR8 )1-3 、-NR8 R9 、-C1-6 亞烷基-NR8 R9 、-CN、-C1-6 亞烷基-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-C1-6 亞烷基-C(=O)NR8 R9 、-NR8 C(=O)R8 、-C1-6 亞烷基-NR8 C(=O)R8 或-S(O)2 NR8 R9 ；每個R42 獨立地可選地被1、2、3、4、5或6個選自鹵素、-C1-6 烷基、-C1-6 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 的取代基； 每個R5 和R6 在每次出現時獨立地選自氫、鹵素、-C1-6 烷基、-C2 -6 烯基、-C2 -6 炔基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 或-C3-10 碳環基、每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、S、S=O或S(=O)2 的雜原子；每個R5 或R6 在每次出現時獨立地可選地被1、2、3、4、5或6個選自鹵素、氧代、-C1-6 烷基、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 個的取代基取代或不被取代； 每個R7 在每次出現時獨立地選自鹵素、-C1-6 烷基、-C1-6 亞烷基-(鹵素)1-3 、雜C1-6 烷基、-C2-6 烯基、-C2-6 炔基、氧代、-OR8 、-C1-6 亞烷基-(OR8 )1-3 、-O-C1-6 亞烷基-(鹵素)1-3 、-NR8 R9 、-C1-6 亞烷基-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 、-C6-10 芳基、5-10元雜芳基、3-10元雜環基或-C3-10 碳環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、S、S=O或S(=O)2 的雜原子；每個R7 在每次出現時獨立地可選地被1、2、3、4、5或6個選自鹵素、氧代、-C1-6 烷基、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 個取代基取代或不取代； 每個R8 和R9 在每次出現時獨立地選自氫或-C1-6 烷基，每個R8 或R9 獨立地可選地被1、2、3、4、5或6個R10 取代或不取代；或 R8 和R9 與它們共同連接的N原子一起形成3-10元雜環，所述的3-10元雜環可進一步包含1、2、3或4個選自N、O、S、S(=O)或S(=O)2 的雜原子，且所述的3-10元雜環獨立地可選地被1、2、3、4、5或6個R10 取代或不取代； 每個R10 在每次出現時獨立地選自鹵素、氧代、-C1-6 烷基、-C1-6 亞烷基-(鹵素)1-3 、C1-6 雜烷基、-CN、-OH、-OC1-6 烷基、-C1-6 亞烷基-(OH)1-3 、-C1-6 亞烷基-(OC1-6 烷基)1-3 、-NH2 、-NHC1-6 烷基、-N(C1-6 烷基)2 、-C1-6 亞烷基-NH2 、-C1-6 亞烷基-NHC1-6 烷基、-C1-6 亞烷基-N(C1-6 烷基)2 、-C(=O)C1-6 烷基、-C(=O)OC1-6 烷基、-OC(=O)C1-6 烷基、-C(=O)NH2 、-C(=O)NHC1-6 烷基、-C(=O)N(C1-6 烷基)2 、-NHC(=O)C1-6 烷基、-N(C1-6 烷基)C(=O)C1-6 烷基、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 NHC1-6 烷基、-S(O)2 N(C1-6 烷基)或-C3-6 碳環基； m選自0、1、2、3、4、5或6； r選自0、1、2、3、4、5或6； s選自0、1、2、3、4、5或6； p選自0、1、2、3、4、5或6； q選自0、1、2、3、4、5或6。In one aspect, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is provided:
Figure 02_image007
(I) wherein each L 1 is independently selected at each occurrence from absent, (CR 5 R 6 ) m , C(=O), O, NR 8 , S, S(=O), or S( =0) 2 ; each R 1 at each occurrence is independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 6-10 aryl base, -C 1-6 alkylene-C 6-10 aryl, 5-10-membered heteroaryl, -C 1-6 alkylene-(5-10-membered heteroaryl), 3-10-membered heteroaryl Cyclyl, -C 1-6 alkylene-(3-10 membered heterocyclyl), -C 3-10 carbocyclyl, or -C 1-6 alkylene-C 3-10 carbocyclyl, each heterocyclyl and heteroaryl independently comprises three or four at each occurrence selected from N, O, S, S = O or S (= O) 2 heteroatoms; each R 1 is the Each occurrence is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R 11 or with 1, 2, 3, 4, 5 or 6 R 12 or not; each R 11 at each occurrence is independently selected from -C 6-10 aryl, -C 1-6 alkylene-C 6-10 aryl, 5-10 membered heteroaryl, -C 1-6 alkylene -(5-10 membered heteroaryl), 3-10 membered heterocyclyl, -C 1-6 alkylene-(3-10 membered heterocyclyl), -C 3-10 carbocyclyl or -C 1 -6 alkylene-C 3-10 carbocyclyl; each R 11 is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R 12 ; each R 12 is in each independently selected at the first occurrence from halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , C 1-6 heteroalkyl, -CN, -OR 8 , -C 1-6 alkylene-(OR 8 ) 1-3 , -OC 1-6 alkylene-(halogen) 1-3 , -SR 8 , -SC 1-6 alkylene-(halogen) 1-3 , -NR 8 R 9 , -C 1-6 alkylene -NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 or -C 3-6 carbocyclyl; each R 12 independently can be optionally by 1, 2, 3, 4, 5 or 6 selected from halogen, -C 1-6 alkyl, -C 1-6 alkoxy, oxo, -OR 8 , -NR 8 R 9 , - CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 substituents substituted or unsubstituted; each R 2 at each occurrence is independently selected from halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , C 1-6 heteroalkyl, -CN, -OR 8 , -C 1-6 alkylene-(OR 8 ) 1-3 , -NR 8 R 9 , -C 1-6 alkylene -NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O ) NR 8 R 9 , -NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 , or -C 3-6 carbocyclyl; each R 2 is independently optionally 2, 3, 4, 5 or 6 are selected from halogen, -C 1-6 alkyl, -C 1-6 alkoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C( =O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S( O) 2 NR 8 R 9 substituents substituted or unsubstituted; each L 3 at each occurrence is independently selected from absent, (CR 5 R 6 ) m , C(=O), O, NR 8 , S, S(=O) or S(=O) 2 ; each ring A is a C 3-10 carbocycle, the
Figure 02_image010
and
Figure 02_image012
may be attached to the same carbon atom or to a different atom of said Ring A; each R 3 is -OR 8 , -NR 8 R 9 , -SR 8 , -S(=O)R 8 , -S( =0) 2 R 8 , 5-10 membered heteroaryl or 3-10 membered heterocyclyl, each heterocyclyl and heteroaryl independently at each occurrence contains 1, 2, 3 or 4 selected from A heteroatom of N, O, S, S=O or S(=O) 2 , each R 3 is independently optionally substituted at each occurrence by 1, 2, 3, 4, 5 or 6 R 10 or unsubstituted; each L 4 is independently at each occurrence selected from absent, (CR 5 R 6) m , C (= O), O, NR 8, S, S (= O) or S (= O) 2 ; each R 4 at each occurrence is independently selected from
Figure 02_image014
,
Figure 02_image016
,
Figure 02_image018
or
Figure 02_image020
, each R 4 is independently optionally substituted or unsubstituted with 1 , 2 , 3 , 4 , 5 or 6 R 42 at each occurrence; each G 1 , G 2 , G 3 and G 4 is when occurrence is independently selected from N or CR 5; each of n1, n2, n3, n4, n5 are independently selected from 4, 5 or 6 at each occurrence, with the proviso that n1 and n2 is not both 0, n3 and n4 are not both 0; each R 41 at each occurrence is independently selected from
Figure 02_image022
; Each Q is independently at each occurrence selected from C (= O), NR 8 C (= O), S (= O) 2 or NR 8 S (= O) 2 ;
Figure 02_image024
selected from
Figure 02_image026
or
Figure 02_image028
; when
Figure 02_image024
selected from
Figure 02_image026
, each R 4a , R 4b and R 4c at each occurrence is independently selected from hydrogen, halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1- 3 , C 1-6 heteroalkyl, -CN, -OR 8 , -C 1-6 alkylene-(OR 8 ) 1-3 , -NR 8 R 9 , -C 1-6 alkylene-NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -C 1-6 alkylene -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -C 1-6 alkylene-NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 or -C 3-10 carbocyclyl; each R 4a , R 4b and R 4c independently optionally by 1, 2, 3, 4, 5 or 6 selected from halogen, -C 1-6 alkyl , -C 1-6 alkoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O) Substituents of R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 , substituted or unsubstituted; or R 4b and R 4c The carbon atoms to which they are commonly attached form a C 3-10 carbocycle or a 3-10 membered heterocycle, each heterocycle containing at each occurrence 1, 2 or 3 atoms selected from N, O, S, SO or A heteroatom of S(O) 2 , and each carbocyclyl or heterocycle may be replaced by 1, 2, 3, 4, 5, or 6 selected from halogen, -C 1-6 alkyl, -C 1-6 alkane Oxygen, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(= O) Substituents of NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 are substituted or unsubstituted; or when
Figure 02_image024
selected from
Figure 02_image028
, each R 4a is absent, and one of R 4b and R 4c is selected from absent, and the other of R 4b and R 4c is selected from hydrogen, halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , C 1-6 heteroalkyl, -CN, -OR 8 , -C 1-6 alkylene-(OR 8 ) 1-3 , -NR 8 R 9 , -C 1-6 alkylene -NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O ) NR 8 R 9 , -C 1-6 alkylene-C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -C 1-6 alkylene-NR 8 C(= O)R 8 , -S(O) 2 NR 8 R 9 or -C 3-10 carbocyclyl; each R 4b or R 4c is independently optionally replaced by 1, 2, 3, 4, 5 or 6 Selected from halogen, -C 1-6 alkyl, -C 1-6 alkoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(= Substituent substitution of O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 or -S(O) 2 NR 8 R 9 or unsubstituted; each R 42 is selected from halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , C 1-6 heteroalkyl, -C 2 -6 alkenyl, -C 2-6 alkynyl, -OR 8 , -C 1-6 alkylene-(OR 8 ) 1-3 , -NR 8 R 9 , -C 1-6 alkylene-NR 8 R 9 , -CN, -C 1-6 alkylene-CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O ) NR 8 R 9 , -C 1-6 alkylene-C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -C 1-6 alkylene-NR 8 C(= O)R 8 or -S(O) 2 NR 8 R 9 ; each R 42 is independently optionally 1, 2, 3, 4, 5 or 6 selected from halogen, -C 1-6 alkyl, -C 1-6 alkoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8, -C (= O) NR 8 R 9, -NR 8 C (= O) R 8, or -S (O) 2 NR 8 R 9 substituents; each R 5 and R 6 at each occurrence, is independently selected from hydrogen, halogen, -C 1-6 alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O) R 8, -S (O) 2 NR 8 R 9 , or -C 3-10 carbocyclic group, a heterocyclic group, and each heteroaryl groups containing 3 or 4 independently at each occurrence selected from Heteroatoms of N, O, S, S=O or S(=O) 2 ; each R 5 or R 6 at each occurrence is independently optionally replaced by 1, 2, 3, 4, 5 or 6 Selected from halogen, oxo, -C 1-6 alkyl, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(= O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 substituents are substituted or unsubstituted; each R 7 is at each occurrence independently selected from halogen, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , heteroC 1-6 alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, oxo, -OR 8 , -C 1-6 alkylene-(OR 8 ) 1-3 , -OC 1-6 alkylene-(halogen) 1-3 , -NR 8 R 9 , -C 1-6 alkylene -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 , -C 6-10 aryl, 5-10-membered heteroaryl, 3-10 membered heterocyclyl or -C 3-10 carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence 1, 2, 3 or 4 selected from N, O, S, S = O or S (= O) 2 heteroatoms; each R 7 is independently at each occurrence, optionally 5 or 6 is selected from halo, oxo, -C 1-6 alkyl, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(= O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 substituents substituted or unsubstituted; each R 8 and R 9 are independently at each occurrence is selected from hydrogen or -C 1-6 alkyl, each R 8 or R 9 is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R 10 ; or R 8 and R 9 together with the N atoms to which they are connected together form a 3-10 membered heterocycle, and the 3-10 membered heterocycle may further comprise 1, 2, 3 or 4 selected from N, O, S, S(=O) Or a heteroatom of S(=O) 2 , and the 3-10-membered heterocyclic ring is independently optionally replaced by 1, 2 , 3, 4, 5 or 6 R 10 substituted or unsubstituted; each R 10 at each occurrence is independently selected from halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene -(Halogen) 1-3 , C 1-6 heteroalkyl, -CN, -OH, -OC 1-6 alkyl, -C 1-6 alkylene-(OH) 1-3 , -C 1- 6 alkylene-(OC 1-6 alkyl) 1-3 , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-6 alkylene- NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl) 2 , -C(=O)C 1-6 alkane base, -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6 alkyl, -C(=O)NH 2 , -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl) 2 , -NHC(=O)C 1-6 alkyl, -N(C 1-6 alkyl)C(=O)C 1-6 alkane base, -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 NHC 1-6 alkyl, -S(O) 2 N(C 1-6 alkyl ) or -C 3-6 carbocyclyl; m is selected from 0, 1, 2, 3, 4, 5 or 6; r is selected from 0, 1, 2, 3, 4, 5 or 6; s is selected from 0, 1, 2, 3, 4, 5 or 6; p is selected from 0, 1, 2, 3, 4, 5 or 6; q is selected from 0, 1, 2, 3, 4, 5 or 6.

在一些實施方式中，每個L1 在每次出現時獨立地選自不存在或(CR5 R6 )m 。In some embodiments, each L 1 is independently selected at each occurrence from absent or (CR 5 R 6 ) m .

在一些實施方式中，每個L1 在每次出現時獨立地選自不存在。In some embodiments, each L 1 is independently selected from absence at each occurrence.

在一些實施方式中，每個R1 在每次出現時獨立地選自氫、-C1-3 烷基、-C2-3 烯基、-C2-3 炔基、-C6-10 芳基、-C1-3 亞烷基-C6-10 芳基、5-10元雜芳基、-C1-3 亞烷基-(5-10元雜芳基)、3-6元雜環基、-C1-3 亞烷基-(3-6元雜環基)、-C3-6 碳環基或-C1-3 亞烷基-C3-6 碳環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個R1 在每次出現時獨立地可選地被1、2、3、4、5或6個R11 取代或不取代或1、2、3、4、5或6個R12 取代或不取代。In some embodiments, each R 1 is independently selected at each occurrence from hydrogen, -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 6-10 Aryl, -C 1-3 alkylene-C 6-10 aryl, 5-10-membered heteroaryl, -C 1-3 alkylene-(5-10-membered heteroaryl), 3-6 membered Heterocyclyl, -C 1-3 alkylene-(3-6 membered heterocyclyl), -C 3-6 carbocyclyl or -C 1-3 alkylene-C 3-6 carbocyclyl, each heterocyclyl and heteroaryl groups comprising independently at each occurrence 2, 3 or 4 heteroatoms selected from N, O, or S heteroatom; each R 1 is independently at each occurrence optionally Substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R 11 or substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R 12 .

在一些實施方式中，每個R1 在每次出現時獨立地選自氫、甲基、乙基、丙基、異丙基、乙烯基、丙烯基、異丙烯基、乙炔基、丙炔基、異丙炔基、苯基、萘基、-亞甲基-C6-10 芳基、-亞乙基-C6-10 芳基、-亞丙基-C6-10 芳基、-亞異丙基-C6-10 芳基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基、10元雜芳基、-亞甲基-(5-10元雜芳基)、-亞乙基-(5-10元雜芳基)、-亞丙基-(5-10元雜芳基)、-亞異丙基-(5-10元雜芳基)、3元雜環基、4元雜環基、5元雜環基、6元雜環基、-亞甲基-(3-6元雜環基)、-亞乙基-(3-6元雜環基)、-亞丙基-(3-6元雜環基)、-亞異丙基-(3-6元雜環基)、3元碳環基、4元碳環基、5元碳環基、6元碳環基、-亞甲基-C3-6 碳環基、-亞乙基-C3-6 碳環基、-亞丙基-C3-6 碳環基或-亞異丙基-C3-6 碳環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個R1 在每次出現時獨立地可選地被1、2、3、4、5或6個R11 取代或不取代或1、2、3、4、5或6個R12 取代或不取代。In some embodiments, each R 1 is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, isopropenyl, ethynyl, propynyl , isopropynyl, phenyl, naphthyl, -methylene-C 6-10 aryl, - ethylene-C 6-10 aryl, - propylene-C 6-10 aryl, - ethylene Isopropyl-C 6-10 aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, -methylene base-(5-10-membered heteroaryl), -ethylene-(5-10-membered heteroaryl), -propylene-(5-10-membered heteroaryl), -isopropylidene-(5 -10-membered heteroaryl), 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene-(3-6 membered heterocyclyl), -ethylene base-(3-6 membered heterocyclyl), -propylene-(3-6 membered heterocyclyl), -isopropylidene-(3-6 membered heterocyclyl), 3 membered carbocyclyl, 4 membered carbocyclic 5-membered carbocyclic group, a 6-membered carbocyclic group, - a methylene group -C 3-6 carbocyclic group, - ethylene -C 3-6 carbocyclic group, - propylene -C 3 -6 carbocyclyl or -isopropylidene-C 3-6 carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence 1, 2, 3 or 4 selected from N, O , or a heteroatom of S; each R 1 at each occurrence is independently optionally substituted or unsubstituted or 1, 2, 3, 4, 5 by 1, 2, 3, 4, 5, or 6 R 11 s or 6 R 12 substituted or unsubstituted.

在一些實施方式中，每個R1 在每次出現時獨立地選自苯基、萘基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基或10元雜芳基，每個雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個R1 在每次出現時獨立地可選地被1、2、3、4、5或6個R11 取代或不取代或1、2、3、4、5或6個R12 取代或不取代。In some embodiments, each R 1 is independently selected at each occurrence from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl membered heteroaryl or 10-membered heteroaryl, each heteroaryl group contains 3 or 4 is independently selected from N, at each occurrence, O, S, or a heteroatom; each R 1 is on each is independently optionally occurrence when 5 or 6 is R 11 or a substituted or unsubstituted 5 or 6 unsubstituted or substituted with R 12.

在一些實施方式中，每個R1 在每次出現時獨立地選自苯基或萘基，每個R1 在每次出現時獨立地可選地被1、2、3、4、5或6個R11 取代或不取代或1、2、3、4、5或6個R12 取代或不取代。In some embodiments, each R 1 at each occurrence is independently selected from phenyl or naphthyl, and each R 1 at each occurrence is independently optionally selected from 1, 2, 3, 4, 5, or 6 R 11 substituted or unsubstituted or 1, 2, 3, 4, 5 or 6 R 12 substituted or unsubstituted.

在一些實施方式中，每個R1 在每次出現時獨立地選自苯基、萘基、吡啶基、吲哚基、吲唑基、吲哚嗪基、苯并噻唑、苯并異噻唑、喹唑啉、異喹唑啉或鄰苯二甲醯基，每個R1 在每次出現時獨立地可選地被1、2、3、4、5或6個R11 取代或不被取代或1、2、3、4、5或6個R12 取代或不被取代。In some embodiments, each R 1 is independently at each occurrence selected from phenyl, naphthyl, pyridyl, indolyl, indazolyl, indolizinyl, benzothiazole, benzisothiazole, quinazoline, isoquinoline or quinazoline phthaloyl acyl, each R 1 is independently at each occurrence optionally substituted 5 or 6 R 11 substituted or unsubstituted or 1, 2, 3, 4, 5 or 6 R 12 substituted or unsubstituted.

在一些實施方式中，每個R11 在每次出現時獨立地選自-C6-10 芳基、-C1-3 亞烷基-C6-10 芳基、5-10元雜芳基、-C1-3 亞烷基-(5-10元雜芳基)、3-6元雜環基、-C1-3 亞烷基-(3-6元雜環基)、-C3-6 碳環基或-C1-3 亞烷基-C3-6 碳環基；每個R11 獨立地可選地被1、2、3、4、5或6個R12 取代或不被取代。In some embodiments, each R 11 at each occurrence is independently selected from -C 6-10 aryl, -C 1-3 alkylene-C 6-10 aryl, 5-10 membered heteroaryl , -C 1-3 alkylene-(5-10 membered heteroaryl), 3-6 membered heterocyclyl, -C 1-3 alkylene-(3-6 membered heterocyclyl), -C 3 -6 carbocyclyl or -C 1-3 alkylene-C 3-6 carbocyclyl; each R 11 is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R 12 or not be replaced.

在一些實施方式中，每個R11 在每次出現時獨立地選自苯基、萘基、-亞甲基-C6-10 芳基、-亞乙基-C6-10 芳基、-亞丙基-C6-10 芳基、-亞異丙基-C6-10 芳基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基、10元雜芳基、-亞甲基-(5-10元雜芳基)、-亞乙基-(5-10元雜芳基)、-亞丙基-(5-10元雜芳基)、-亞異丙基-(5-10元雜芳基)、3元雜環基、4元雜環基、5元雜環基、6元雜環基、-亞甲基-(3-6元雜環基)、-亞乙基-(3-6元雜環基)、-亞丙基-(3-6元雜環基)、-亞異丙基-(3-6元雜環基)、3元碳環基、4元碳環基、5元碳環基、6元碳環基、-亞甲基-C3-6 碳環基、-亞乙基-C3-6 碳環基、-亞丙基-C3-6 碳環基或-亞異丙基-C3-6 碳環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個R11 在每次出現時獨立地可選地被1、2、3、4、5或6個R12 取代或不取代。In some embodiments, each R 11 is independently selected at each occurrence from phenyl, naphthyl, -methylene-C 6-10 aryl, -ethylene-C 6-10 aryl, - Propylene-C 6-10 aryl, -isopropylidene-C 6-10 aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered Heteroaryl, 10-membered heteroaryl, -methylene-(5-10-membered heteroaryl), -ethylene-(5-10-membered heteroaryl), -propylene-(5-10-membered) Heteroaryl), -isopropylidene-(5-10-membered heteroaryl), 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene- (3-6 membered heterocyclyl), -Ethylene-(3-6 membered heterocyclyl), -Propylene-(3-6 membered heterocyclyl), -Isopropylidene-(3-6 membered heterocyclyl), 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, -methylene-C 3-6 carbocyclyl, -ethylene-C 3 -6- carbocyclyl, -propylene- C3-6carbocyclyl , or -isopropylidene- C3-6carbocyclyl , each heterocyclyl and heteroaryl independently at each occurrence comprising 2, 3 or 4 heteroatoms selected from N, O, or S heteroatom; each R 11 is independently optionally substituted at each occurrence is 12 5 or 6 R or not to replace.

在一些實施方式中，每個R11 在每次出現時獨立地選自苯基、萘基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基或10元雜芳基，每個雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個R11 在每次出現時獨立地可選地被1、2、3、4、5或6個R12 取代或不被取代。In some embodiments, each R 11 at each occurrence is independently selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl A membered heteroaryl or a 10 membered heteroaryl, each heteroaryl independently at each occurrence contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S; each R 11 in each The next occurrence is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R 12 or not.

在一些實施方式中，每個R1 選自：

Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
、
Figure 02_image047
、
Figure 02_image049
、
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
、
Figure 02_image057
、
Figure 02_image059
、
Figure 02_image061
、
Figure 02_image063
、
Figure 02_image065
、
Figure 02_image067
、
Figure 02_image069
、
Figure 02_image071
或
Figure 02_image073
； 每個R1 在每次出現時獨立地可選地被1、2、3、4、5或6個R12 取代或不取代。In some embodiments, each R 1 is selected from:
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
,
Figure 02_image047
,
Figure 02_image049
,
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
,
Figure 02_image057
,
Figure 02_image059
,
Figure 02_image061
,
Figure 02_image063
,
Figure 02_image065
,
Figure 02_image067
,
Figure 02_image069
,
Figure 02_image071
or
Figure 02_image073
; Each R 1 is independently in each occurrence optionally be 5 or 6 R 12 substituted or unsubstituted.

在一些實施方式中，每個R1 選自：

Figure 02_image033
或
Figure 02_image041
； 每個R1 在每次出現時獨立地可選地被1、2、3、4、5或6個R12 取代或不被取代。In some embodiments, each R 1 is selected from:
Figure 02_image033
or
Figure 02_image041
; Each R 1 is independently at each occurrence optionally substituted 5 or 6 R 12 substituted or unsubstituted.

在一些實施方式中，每個R12 在每次出現時獨立地選自鹵素、氧代、-C1-3 烷基、-C1-3 亞烷基-(鹵素)1-3 、雜C1-3 烷基、-CN、-OR8 、-C1-3 亞烷基-(OR8 )1-3 、-O-C1-3 亞烷基-(鹵素)1-3 、-SR8 、-S-C1-3 亞烷基-(鹵素)1-3 、-NR8 R9 、-C1-3 亞烷基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 或-C3-6 碳環基；每個R12 獨立地可選地被1、2、3、4、5或6個選自鹵素、-C1-3 烷基、-C1-3 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R12 中的R8 和R9 在每次出現時獨立地選自氫或-C1-3 烷基。In some embodiments, each R 12 is independently selected at each occurrence from halogen, oxo, -C 1-3 alkyl, -C 1-3 alkylene-(halogen) 1-3 , heteroC 1-3 alkyl, -CN, -OR 8 , -C 1-3 alkylene-(OR 8 ) 1-3 , -OC 1-3 alkylene-(halogen) 1-3 , -SR 8 , -SC 1-3 alkylene-(halogen) 1-3 , -NR 8 R 9 , -C 1-3 alkylene-NR 8 R 9 , -C(=O)R 8 , -C(=O )OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 or -C 3- 6- carbocyclyl; each R 12 is independently optionally replaced by 1, 2, 3, 4, 5 or 6 selected from halogen, -C 1-3 alkyl, -C 1-3 alkoxy, oxo , -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 or -S(O) 2 NR 8 R 9 is substituted or unsubstituted; R 8 and R 9 in each R 12 are independently selected at each occurrence From hydrogen or -C 1-3 alkyl.

在一些實施方式中，每個R12 在每次出現時獨立地選自-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、-亞甲基-(鹵素)1-3 、-亞乙基-(鹵素)1-3 、-亞丙基-(鹵素)1-3 、雜甲基、雜乙基、雜丙基、-CN、-OR8 、-亞甲基-(OR8 )1-3 、-亞乙基-(OR8 )1-3 、-亞丙基-(OR8 )1-3 、-O-亞甲基-(鹵素)1-3 、-O-亞乙基-(鹵素)1-3 、-O-亞丙基-(鹵素)1-3 、-SR8 、-S-亞甲基-(鹵素)1-3 、-S-亞乙基-(鹵素)1-3 、-S-亞丙基-(鹵素)1-3 、-NR8 R9 、-亞甲基-NR8 R9 、-亞乙基-NR8 R9 、-亞丙基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 、3元碳環基、4元碳環基、或5元碳環基或6元碳環基；每個R12 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R12 中的R8 和R9 在每次出現時獨立地選自氫、甲基、乙基、丙基或異丙基。In some embodiments, each R 12 at each occurrence is independently selected from -F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, - methylene - ( halogen) 1-3 , -ethylene-(halogen) 1-3 , -propylene-(halogen) 1-3 , heteromethyl, heteroethyl, heteropropyl, -CN, -OR 8 , - Methylene-(OR 8 ) 1-3 , -ethylene-(OR 8 ) 1-3 , -propylene-(OR 8 ) 1-3 , -O-methylene-(halogen) 1- 3 , -O-ethylene-(halogen) 1-3 , -O-propylene-(halogen) 1-3 , -SR 8 , -S-methylene-(halogen) 1-3 , -S -Ethylene-(halogen) 1-3 , -S-propylene-(halogen) 1-3 , -NR 8 R 9 , -methylene-NR 8 R 9 , -ethylene-NR 8 R 9 , -propylene-NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C (= O) R 8, -S (O) 2 NR 8 R 9, 3 -membered carbocyclic ring group, 4-membered carbocyclic ring group, or 5-membered carbocyclic group or a 6-membered carbocyclic group; each R 12 is independently optionally replaced by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy , propoxy, isopropoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O) Substituents of R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 or -S(O) 2 NR 8 R 9 are substituted or unsubstituted; R in each R 12 8 and R 9 at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

在一些實施方式中，每個R12 在每次出現時獨立地選自-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CH2 F、-OCH2 CHF2 、-OCH2 CF3 、-OCH2 CH2 CH2 F、-OCH2 CH2 CHF2 、-OCH2 CH2 CF3 、-SH、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-SCH2 F、-SCHF2 、-SCF3 、-SCH2 CH2 F、-SCH2 CHF2 、-SCH2 CF3 、-SCH2 CH2 CH2 F、-SCH2 CH2 CHF2 、-SCH2 CH2 CF3 、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 N(CH3 )2 、3元碳環基、4元碳環基、5元碳環基或6元碳環基；每個R12 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OH、-NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 的取代基取代或不取代。In some embodiments, each R 12 at each occurrence is independently selected from -F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, - CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH (CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -OCH 2 F, -OCHF 2, -OCF 3, -OCH 2 CH 2 F, -OCH 2 CHF 2, -OCH 2 CF 3 , -OCH 2 CH 2 CH 2 F, -OCH 2 CH 2 CHF 2, -OCH 2 CH 2 CF 3, -SH, -SCH 3, -SCH 2 CH 3, -SCH (CH 3) 2, -SCH 2 F, -SCHF 2, -SCF 3, -SCH 2 CH 2 F, -SCH 2 CHF 2, -SCH 2 CF 3, -SCH 2 CH 2 CH 2 F, -SCH 2 CH 2 CHF 2, -SCH 2 CH 2 CF 3, -NH 2, -NHCH 3, -NHCH 2 CH 3, -NHCH 2 CH 2 CH 3, -NHCH (CH 3) 2, -N (CH 3) 2 , -N (CH 3) CH 2 CH 3, -N (CH 3) CH 2 CH 2 CH 3, -N (CH 3) CH (CH 3) 2, -CH 2 NH 2, -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -C (=O)CH 3 , -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , - C(=O)NH 2 , -C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N(CH 3 ) 2 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; each R 12 is independently optionally replaced by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CN, -C(=O)CH 3 , -C(=O)OCH 3 , -OC(=O)CH 3 , -C( =O)NH 2 , -C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C(=O )CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ) or -S(O) 2 N(CH 3 ) 2 is substituted or unsubstituted.

在一些實施方式中，每個R12 在每次出現時獨立地選自-F、-Cl、-OH、-NH2 、-CN、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、-CF3 、-OCF3 、-OCH2 OCH3 、-NH(CH3 )、-N(CH3 )2 、-COCH3 、-COCF3 、-OCOCH3 、-OCOCF3 、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-CH2 OCH3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 或3元碳環基。In some embodiments, each R 12 at each occurrence is independently selected from -F, -Cl, -OH, -NH 2 , -CN, methyl, ethyl, propyl, isopropyl, methoxy group, ethoxy, propoxy, isopropoxy, -CF 3 , -OCF 3 , -OCH 2 OCH 3 , -NH(CH 3 ), -N(CH 3 ) 2 , -COCH 3 , -COCF 3, -OCOCH 3, -OCOCF 3, -CH 2 F, -CHF 2, -CF 3, -CH 2 CH 2 F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F , -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 OCH 3, -CH 2 OCH 3, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 or 3-membered carbocyclyl.

在一些實施方式中，每個R1 選自：

Figure 02_image033
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
、
Figure 02_image130
、
Figure 02_image132
、
Figure 02_image134
、
Figure 02_image136
、
Figure 02_image138
、
Figure 02_image140
、
Figure 02_image142
、
Figure 02_image144
、
Figure 02_image146
、
Figure 02_image148
、
Figure 02_image150
、
Figure 02_image152
、
Figure 02_image154
、
Figure 02_image156
、
Figure 02_image158
、
Figure 02_image160
、
Figure 02_image162
、
Figure 02_image164
、
Figure 02_image166
、
Figure 02_image168
、
Figure 02_image170
、
Figure 02_image172
、
Figure 02_image174
、
Figure 02_image176
、
Figure 02_image178
、
Figure 02_image180
、
Figure 02_image182
、
Figure 02_image184
、
Figure 02_image186
、
Figure 02_image188
、
Figure 02_image190
、
Figure 02_image192
、
Figure 02_image194
、
Figure 02_image196
、
Figure 02_image198
、
Figure 02_image200
、
Figure 02_image202
、
Figure 02_image204
、
Figure 02_image206
、
Figure 02_image208
、
Figure 02_image210
、
Figure 02_image212
、
Figure 02_image214
、
Figure 02_image216
、
Figure 02_image218
、
Figure 02_image220
、
Figure 02_image222
、
Figure 02_image224
、
Figure 02_image226
、
Figure 02_image228
、
Figure 02_image230
、
Figure 02_image232
、
Figure 02_image234
、
Figure 02_image236
、
Figure 02_image238
、
Figure 02_image240
、
Figure 02_image242
、
Figure 02_image244
、
Figure 02_image246
、
Figure 02_image248
、
Figure 02_image250
、
Figure 02_image252
、
Figure 02_image254
、
Figure 02_image256
、
Figure 02_image258
、
Figure 02_image260
、
Figure 02_image262
、
Figure 02_image264
、
Figure 02_image266
、
Figure 02_image268
、
Figure 02_image270
、
Figure 02_image047
、
Figure 02_image049
、
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image276
、
Figure 02_image278
、
Figure 02_image055
、
Figure 02_image057
、
Figure 02_image059
、
Figure 02_image283
、
Figure 02_image285
、
Figure 02_image287
、
Figure 02_image289
、
Figure 02_image067
、
Figure 02_image292
、
Figure 02_image294
、
Figure 02_image296
、
Figure 02_image298
、
Figure 02_image300
、
Figure 02_image302
、
Figure 02_image304
、
Figure 02_image306
、
Figure 02_image308
、
Figure 02_image310
、
Figure 02_image312
、
Figure 02_image314
、
Figure 02_image316
、
Figure 02_image318
、
Figure 02_image320
、
Figure 02_image322
、
Figure 02_image324
、
Figure 02_image326
、
Figure 02_image328
、
Figure 02_image330
、
Figure 02_image332
、
Figure 02_image306
、
Figure 02_image310
、
Figure 02_image312
、
Figure 02_image308
、
Figure 02_image314
、
Figure 02_image316
、
Figure 02_image318
、
Figure 02_image320
、
Figure 02_image322
、
Figure 02_image324
、
Figure 02_image326
、
Figure 02_image344
、
Figure 02_image346
、
Figure 02_image348
、
Figure 02_image350
、
Figure 02_image352
、
Figure 02_image354
、
Figure 02_image356
 或
Figure 02_image358
。    In some embodiments, each R 1 is selected from:
Figure 02_image033
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
,
Figure 02_image130
,
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
,
Figure 02_image144
,
Figure 02_image146
,
Figure 02_image148
,
Figure 02_image150
,
Figure 02_image152
,
Figure 02_image154
,
Figure 02_image156
,
Figure 02_image158
,
Figure 02_image160
,
Figure 02_image162
,
Figure 02_image164
,
Figure 02_image166
,
Figure 02_image168
,
Figure 02_image170
,
Figure 02_image172
,
Figure 02_image174
,
Figure 02_image176
,
Figure 02_image178
,
Figure 02_image180
,
Figure 02_image182
,
Figure 02_image184
,
Figure 02_image186
,
Figure 02_image188
,
Figure 02_image190
,
Figure 02_image192
,
Figure 02_image194
,
Figure 02_image196
,
Figure 02_image198
,
Figure 02_image200
,
Figure 02_image202
,
Figure 02_image204
,
Figure 02_image206
,
Figure 02_image208
,
Figure 02_image210
,
Figure 02_image212
,
Figure 02_image214
,
Figure 02_image216
,
Figure 02_image218
,
Figure 02_image220
,
Figure 02_image222
,
Figure 02_image224
,
Figure 02_image226
,
Figure 02_image228
,
Figure 02_image230
,
Figure 02_image232
,
Figure 02_image234
,
Figure 02_image236
,
Figure 02_image238
,
Figure 02_image240
,
Figure 02_image242
,
Figure 02_image244
,
Figure 02_image246
,
Figure 02_image248
,
Figure 02_image250
,
Figure 02_image252
,
Figure 02_image254
,
Figure 02_image256
,
Figure 02_image258
,
Figure 02_image260
,
Figure 02_image262
,
Figure 02_image264
,
Figure 02_image266
,
Figure 02_image268
,
Figure 02_image270
,
Figure 02_image047
,
Figure 02_image049
,
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image276
,
Figure 02_image278
,
Figure 02_image055
,
Figure 02_image057
,
Figure 02_image059
,
Figure 02_image283
,
Figure 02_image285
,
Figure 02_image287
,
Figure 02_image289
,
Figure 02_image067
,
Figure 02_image292
,
Figure 02_image294
,
Figure 02_image296
,
Figure 02_image298
,
Figure 02_image300
,
Figure 02_image302
,
Figure 02_image304
,
Figure 02_image306
,
Figure 02_image308
,
Figure 02_image310
,
Figure 02_image312
,
Figure 02_image314
,
Figure 02_image316
,
Figure 02_image318
,
Figure 02_image320
,
Figure 02_image322
,
Figure 02_image324
,
Figure 02_image326
,
Figure 02_image328
,
Figure 02_image330
,
Figure 02_image332
,
Figure 02_image306
,
Figure 02_image310
,
Figure 02_image312
,
Figure 02_image308
,
Figure 02_image314
,
Figure 02_image316
,
Figure 02_image318
,
Figure 02_image320
,
Figure 02_image322
,
Figure 02_image324
,
Figure 02_image326
,
Figure 02_image344
,
Figure 02_image346
,
Figure 02_image348
,
Figure 02_image350
,
Figure 02_image352
,
Figure 02_image354
,
Figure 02_image356
 or
Figure 02_image358
.

在一些實施方式中，每個R2 在每次出現時獨立地選自-F、-Cl、-Br、氧代、-C1-3 烷基、-C1-3 亞烷基-(鹵素)1-3 、C1-3 雜烷基、-CN、-OR8 、-C1-3 亞烷基-(OR8 )1-3 、-NR8 R9 、-C1-3 亞烷基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 、3元碳環基、4元碳環基、5元碳環基或6元碳環基；每個R2 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、-C1-3 烷基、-C1-3 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R2 中的R8 和R9 在每次出現時獨立地選自氫或-C1-3 烷基。In some embodiments, each of R 2 at each occurrence is independently selected from -F, -Cl, -Br, oxo, -C 1-3 alkyl, -C 1-3 alkylene - (halo ) 1-3 , C 1-3 heteroalkyl, -CN, -OR 8 , -C 1-3 alkylene -(OR 8 ) 1-3 , -NR 8 R 9 , -C 1-3 alkylene Base -NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C( =O)R 8 , -S(O) 2 NR 8 R 9 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; each R 2 is independently optionally by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, -Br, -C 1-3 alkyl, -C 1-3 alkoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C( Substituents of =O)R 8 , or -S(O) 2 NR 8 R 9 are substituted or unsubstituted; R 8 and R 9 in each R 2 are independently selected at each occurrence from hydrogen or -C 1 -3 alkyl.

在一些實施方式中，每個R2 在每次出現時獨立地選自-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 N(CH3 )2 、3元碳環基、4元碳環基、5元碳環基或6元碳環基；每個R2 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OH、-NH2 、-N(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 的取代基取代或不取代。In some embodiments, each of R 2 at each occurrence is independently selected from -F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, - CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH (CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2, -NHCH 3, -NHCH 2 CH 3, -NHCH 2 CH 2 CH 3, -NHCH (CH 3) 2, -N (CH 3) 2, -N (CH 3) CH 2 CH 3, -N (CH 3) CH 2 CH 2 CH 3, -N (CH 3) CH (CH 3 ) 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , - CH 2 CH 2 CH 2 N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -NHC (=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N( CH 3 ) 2 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; each R 2 is independently optionally replaced by 1, 2, 3, 4, 5, or 6 One is selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH 2 , -N(CH 3 ) 2 , -CN, -C(=O)CH 3 , -C(=O)OCH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , - C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ) or -S( The substituents of O) 2 N(CH 3 ) 2 are substituted or unsubstituted.

在一些實施方式中，每個R2 在每次出現時獨立地選自-F、-Cl、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 或-NHCH(CH3 )2 。In some embodiments, each of R 2 at each occurrence is independently selected from -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2, -CF 3, -OH, -OCH 3, -OCH 2 CH 3, -OCH 2 CH 2 CH 3, -OCH (CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2, -NHCH 3, -NHCH 2 CH 3, -NHCH 2 CH 2 CH 3 or -NHCH (CH 3) 2.

在一些實施方式中，r選自0、1或2。In some embodiments, r is selected from 0, 1 or 2.

在一些實施方式中，r選自0。In some embodiments, r is selected from zero.

在一些實施方式中，每個L3 在每次出現時獨立地選自O、NR8 或S； 每個L3 中的R8 在每次出現時獨立地選自氫或-C1-3 烷基。In some embodiments, each L 3 is independently selected at each occurrence from O, NR 8 or S; the R 8 in each L 3 is independently selected at each occurrence from hydrogen or -C 1-3 alkyl.

在一些實施方式中，每個L3 在每次出現時獨立地選自O、NH、N(CH3 )、N(CH2 CH3 )、N(CH2 CH2 CH3 )、NCH(CH3 )2 或S。In some embodiments, each L 3 is independently at each occurrence selected from O, NH, N (CH 3 ), N (CH 2 CH 3), N (CH 2 CH 2 CH 3), NCH (CH 3 ) 2 or S.

在一些實施方式中，每個L3 在每次出現時獨立地選自O、NH或S。In some embodiments, each L 3 is independently at each occurrence selected from O, NH or S.

在一些實施方式中，每個環A是C3-6 碳環，且所述的

Figure 02_image010
和
Figure 02_image012
可以連接在所述環A的相同的碳原子上或不同的原子上。In some embodiments, each Ring A is a C 3-6 carbocyclic ring, and the
Figure 02_image010
and
Figure 02_image012
The attachment may be on the same carbon atom of the ring A or on a different atom.

在一些實施方式中，每個環A是3元碳環、4元碳環、5元碳環或6元碳環，且所述的

Figure 02_image010
和
Figure 02_image012
可以連接在所述環A的相同的碳原子上或不同的原子上。In some embodiments, each Ring A is a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, or a 6-membered carbocycle, and the
Figure 02_image010
and
Figure 02_image012
The attachment may be on the same carbon atom of the ring A or on a different atom.

在一些實施方式中，每個R3 在每次出現時獨立地選自-OR8 、-NR8 R9 、-SR8 、-S(=O)R8 、-S(=O)2 R8 或3-8元雜環基，每個雜環基在每次出現時獨立地包含1、2、3或4個選自N、O或S的雜原子，每個R3 在每次出現時獨立地可選地被1、2、3、4、5或6個R10 取代或不取代； 每個R3 中的R8 和R9 在每次出現時獨立地選自氫或-C1 -3 烷基；或 R8 和R9 與它們共同連接的N原子一起形成3-8元雜環，所述的3-8元雜環可進一步包含1、2、3或4個選自N、O或S的雜原子，且所述的3-8元雜環獨立地可選地被1、2、3、4、5或6個R10 取代或不被取代。In some embodiments, each R 3 is independently selected at each occurrence from -OR 8 , -NR 8 R 9 , -SR 8 , -S(=O)R 8 , -S(=O) 2 R 8, or 3-8 membered heterocyclyl, each heterocyclyl in each occurrence is independently comprise 2, 3 or 4 hetero atoms selected from N, O or S, each of R 3 in each occurrence, independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R 10 ; R 8 and R 9 in each R 3 are independently selected at each occurrence from hydrogen or -C 1--3 alkyl; or R 8 together form a 3-8 membered heterocyclic ring and R 9 N atom to which they are attached, a 3-8 membered heterocyclic ring may further comprise three or four substituents selected from A heteroatom of N, O or S, and the 3-8 membered heterocycle is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R 10 .

在一些實施方式中，每個R3 在每次出現時獨立地選自-OR8 、-NR8 R9 、-SR8 、-S(=O)R8 、-S(=O)2 R8 或3-6元雜環基，每個雜環基在每次出現時獨立地包含1、2、3或4個選自N、O或S的雜原子，每個R3 在每次出現時獨立地可選地被1、2、3、4、5或6個R10 取代或不被取代； 每個R3 中的R8 和R9 在每次出現時獨立地選自氫或-C1 -3 烷基；或 R8 和R9 與它們共同連接的N原子一起形成3-6元雜環，所述的3-6元雜環可進一步包含1、2、3或4個選自N、O或S的雜原子，且所述的3-6元雜環獨立地可選地被1、2、3、4、5或6個R10 取代或不取代。In some embodiments, each R 3 is independently selected at each occurrence from -OR 8 , -NR 8 R 9 , -SR 8 , -S(=O)R 8 , -S(=O) 2 R 8, or 3-6 membered heterocyclyl, each heterocyclyl in each occurrence is independently comprise 2, 3 or 4 hetero atoms selected from N, O or S, each of R 3 in each occurrence, independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R 10 ; R 8 and R 9 in each R 3 are independently selected at each occurrence from hydrogen or - C 1 - 3 alkyl; or R 8 and R 9 N atom to which they are attached form a 3-6 membered heterocyclic ring said heterocyclic ring can further comprise 3-6 membered, 2, 3 or 4 selected from since hetero atoms N, O or S, and said 3-6 membered heterocyclic ring optionally independently substituted 5 or 6 unsubstituted or substituted with R 10.

在一些實施方式中，每個R3 在每次出現時獨立地選自-NR8 R9 或3-6元雜環基，每個雜環基在每次出現時獨立地包含1個選自N的雜原子，每個R3 在每次出現時獨立地可選地被1、2、3、4、5或6個R10 取代或不被取代； 每個R3 中的R8 和R9 在每次出現時獨立地選自氫、甲基、乙基、丙基或異丙基；或 R3 中的R8 和R9 與它們共同連接的N原子一起形成3-6元雜環，所述的3-6元雜環可進一步包含1選自N的雜原子，且所述的3-6元雜環獨立地可選地被1、2、3、4、5或6個R10 取代或不被取代。In some embodiments, each R 3 at each occurrence is independently selected from -NR 8 R 9 or 3-6 membered heterocyclic group, a heterocyclic group each independently comprise a selected at each occurrence N heteroatoms, each R 3 is independently in each occurrence optionally be 5 or 6 R 10 substituted or unsubstituted; each of R 3 R 8 and R 9 at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl group; or R 3 is R 8 together form a 3-6 membered heterocyclic ring and R 9 N atom to which they are attached , the 3-6 membered heterocycle may further comprise 1 heteroatom selected from N, and the 3-6 membered heterocycle is independently optionally surrounded by 1, 2, 3, 4, 5 or 6 R 10 to replace or not to be substituted.

在一些實施方式中，每個R3 在每次出現時獨立地選自-NH2 、-N(CH3 )2 、-N(CH3 )(CH2 CH3 )、-N(CH2 CH3 )2 、

Figure 02_image363
、
Figure 02_image365
,
Figure 02_image367
、
Figure 02_image369
、
Figure 02_image371
、
Figure 02_image373
、
Figure 02_image375
、
Figure 02_image377
、
Figure 02_image379
或
Figure 02_image381
；每個R3 獨立地可選地被1、2、3、4、5或6個R10 取代或不取代。In some embodiments, each R 3 is independently at each occurrence selected from -NH 2, -N (CH 3) 2, -N (CH 3) (CH 2 CH 3), - N (CH 2 CH 3 ) 2 ,
Figure 02_image363
,
Figure 02_image365
,
Figure 02_image367
,
Figure 02_image369
,
Figure 02_image371
,
Figure 02_image373
,
Figure 02_image375
,
Figure 02_image377
,
Figure 02_image379
or
Figure 02_image381
; Each R 3 is independently optionally substituted 5 or 6 unsubstituted or substituted with R 10.

在一些實施方式中，每個R3 在每次出現時獨立地選自-NH2 、-N(CH3 )2 、-N(CH3 )(CH2 CH3 )、-N(CH2 CH3 )2 、

Figure 02_image363
、
Figure 02_image365
、
Figure 02_image367
、
Figure 02_image369
、
Figure 02_image371
、
Figure 02_image373
、
Figure 02_image375
、
Figure 02_image377
、
Figure 02_image379
、
Figure 02_image381
、
Figure 02_image392
、
Figure 02_image394
,
Figure 02_image396
、
Figure 02_image398
、
Figure 02_image400
；每個R3 獨立地可選地被1、2、3、4、5或6個R10 取代或不被取代。In some embodiments, each R 3 is independently at each occurrence selected from -NH 2, -N (CH 3) 2, -N (CH 3) (CH 2 CH 3), - N (CH 2 CH 3 ) 2 ,
Figure 02_image363
,
Figure 02_image365
,
Figure 02_image367
,
Figure 02_image369
,
Figure 02_image371
,
Figure 02_image373
,
Figure 02_image375
,
Figure 02_image377
,
Figure 02_image379
,
Figure 02_image381
,
Figure 02_image392
,
Figure 02_image394
,
Figure 02_image396
,
Figure 02_image398
,
Figure 02_image400
; Each R 3 is independently optionally substituted 5 or 6 R 10 substituted or unsubstituted.

在一些實施方式中，每個R10 在每次出現時獨立地選自-F、-Cl、-Br、氧代、-C1-3 烷基、-C1-3 亞烷基-(鹵素)1-3 、C1-3 雜烷基、-CN、-OH、-OC1-3 烷基、-C1-3 亞烷基-(OH)1-3 、-C1-3 亞烷基-(OC1-3 烷基)1-3 、-NH2 、-NHC1-3 烷基、-N(C1-3 烷基)2 、-C1-3 亞烷基-NH2 、-C1-3 亞烷基-NHC1-3 烷基、-C1-3 亞烷基-N(C1-3 烷基)2 、-C(=O)C1-3 烷基、-C(=O)OC1-3 烷基、-OC(=O)C1-3 烷基、-C(=O)NH2 、-C(=O)NHC1-3 烷基、-C(=O)N(C1-3 烷基)2 、-NHC(=O)C1-3 烷基、-N(C1-3 烷基)C(=O)C1-3 烷基、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 NHC1-3 烷基、-S(O)2 N(C1-3 烷基)或3元碳環基、4元碳環基、5元碳環基或6元碳環基。In some embodiments, each R 10 is independently selected at each occurrence from -F, -Cl, -Br, oxo, -C 1-3 alkyl, -C 1-3 alkylene-(halogen ) 1-3 , C 1-3 heteroalkyl, -CN, -OH, -OC 1-3 alkyl, -C 1-3 alkylene -(OH) 1-3 , -C 1-3 alkylene base-(OC 1-3 alkyl) 1-3 , -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -C 1-3 alkylene-NH 2 , -C 1-3 alkylene-NHC 1-3 alkyl, -C 1-3 alkylene-N(C 1-3 alkyl) 2 , -C(=O)C 1-3 alkyl, - C(=O)OC 1-3 alkyl, -OC(=O)C 1-3 alkyl, -C(=O)NH 2 , -C(=O)NHC 1-3 alkyl, -C( =O)N(C 1-3 alkyl) 2 , -NHC(=O)C 1-3 alkyl, -N(C 1-3 alkyl) C(=O)C 1-3 alkyl, - S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 NHC 1-3 alkyl, -S(O) 2 N(C 1-3 alkyl) or 3 Carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl.

在一些實施方式中，每個R10 在每次出現時獨立地選自-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2,-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 N(CH3 )2 、3元碳環基、4元碳環基、5元碳環基或6元碳環基。In some embodiments, each R 10 is independently at each occurrence selected from -F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, - CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CH 2 CF 3, -CH 2 OCH 3, -CH 2 CH 2 OCH 3, -CH 2 CH 2 CH 2 OCH 3, -CN, -OH, -OCH 3, -OCH 2 CH 3, -OCH 2 CH 2 CH 3 , -OCH (CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2, -NHCH 3, -NHCH 2 CH 3, -NHCH 2 CH 2 CH 3, -NHCH (CH 3) 2 , -N (CH 3) 2, -N (CH 3) CH 2 CH 3, -N (CH 3) CH 2 CH 2 CH 3, -N (CH 3) CH ( CH 3) 2, -CH 2 NH 2, -CH 2 CH 2 NH 2, -CH 2 CH 2 CH 2 NH 2, -CH 2 N (CH 3) 2, -CH 2 CH 2 N (CH 3) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O) OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , -C(=O)NH2, -C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , - NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N (CH 3 ) 2 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl.

在一些實施方式中，每個R10 在每次出現時獨立地選自-F、-CH3 、-CH(CH3 )2 、-OH或-OCH3 。In some embodiments, each R 10 at each occurrence is independently selected from -F, -CH 3, -CH (CH 3) 2, -OH , or -OCH 3.

在一些實施方式中，每個R3 選自：

Figure 02_image402
、
Figure 02_image404
、
Figure 02_image406
,
Figure 02_image408
、
Figure 02_image410
、
Figure 02_image412
、
Figure 02_image414
、
Figure 02_image416
、
Figure 02_image418
、
Figure 02_image420
、
Figure 02_image422
、
Figure 02_image424
、
Figure 02_image426
、
Figure 02_image428
、
Figure 02_image430
、
Figure 02_image432
、
Figure 02_image434
、
Figure 02_image436
、
Figure 02_image438
、
Figure 02_image440
、
Figure 02_image442
、
Figure 02_image444
、
Figure 02_image446
、
Figure 02_image448
、
Figure 02_image450
或
Figure 02_image452
。In some embodiments, each R 3 is selected from:
Figure 02_image402
,
Figure 02_image404
,
Figure 02_image406
,
Figure 02_image408
,
Figure 02_image410
,
Figure 02_image412
,
Figure 02_image414
,
Figure 02_image416
,
Figure 02_image418
,
Figure 02_image420
,
Figure 02_image422
,
Figure 02_image424
,
Figure 02_image426
,
Figure 02_image428
,
Figure 02_image430
,
Figure 02_image432
,
Figure 02_image434
,
Figure 02_image436
,
Figure 02_image438
,
Figure 02_image440
,
Figure 02_image442
,
Figure 02_image444
,
Figure 02_image446
,
Figure 02_image448
,
Figure 02_image450
or
Figure 02_image452
.

在一些實施方式中，每個R5 和R6 在每次出現時獨立地選自氫、-F、-Cl、-Br、-C1-3 烷基、-C2-3 烯基、-C2-3 炔基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 或-C3-6 碳環基；每個R5 或R6 在每次出現時獨立地可選地被1、2、3、4、5或6個選自鹵素、氧代、-C1-3 烷基、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R5 或R6 中的R8 和R9 獨立地選自氫或-C1-3 烷基。In some embodiments, each R 5 and R 6 are independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -C 1-3 alkyl, -C 2-3 alkenyl, - C 2-3 alkynyl, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C (= O) NR 8 R 9, -NR 8 C (= O) R 8, -S (O) 2 NR 8 R 9 or -C 3-6 carbocyclic group; each of R 5 or R 6 in is independently optionally substituted 5 or 6 substituents selected from halo, oxo, -C 1-3 alkyl, -OR 8, -NR 8 R 9 , -CN each occurrence, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 or - The substituents of S(O) 2 NR 8 R 9 are substituted or unsubstituted; R 8 and R 9 in each R 5 or R 6 are independently selected from hydrogen or -C 1-3 alkyl.

在一些實施方式中，每個R5 和R6 在每次出現時獨立地選自氫、-F、-Cl、-Br、甲基、乙基、丙基、異丙基、乙烯基、丙烯基、異丙烯基、乙炔基、丙炔基、氧代、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 N(CH3 )2 、3元碳環基、4元碳環基、5元碳環基或6元碳環基；每個R5 或R6 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-NH2 、-N(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 的取代基取代或不取代。In some embodiments, each of R 5 and R 6 are independently at each occurrence selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl radical, isopropenyl, ethynyl, propynyl, oxo, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -NH 2 , - NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 3 , -N(CH 3 ) CH 2 CH 2 CH 3 , -N(CH 3 )CH(CH 3 ) 2 , -CN, -C(=O)CH 3 , -C(=O)OCH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C (=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N(CH 3 ) 2 , 3-membered carbocyclyl, 4-membered carbon cycloalkyl group 5-membered carbocyclic group or a 6-membered carbocyclic group; each of R 5 or R 6 are independently optionally substituted 5 or 6 is selected from -F, -Cl, -Br , oxo, methyl, ethyl, propyl, isopropyl, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -NH 2 , -N(CH 3 ) 2 , -CN, -C(=O)CH 3 , -C(=O)OCH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C( =O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -S(O) Substituents of 2 NH 2 , -S(O) 2 NH(CH 3 ) or -S(O) 2 N(CH 3 ) 2 are substituted or unsubstituted.

在一些實施方式中，每個R5 和R6 在每次出現時獨立地選自氫、-F或甲基。In some embodiments, each of R 5 and R 6 is independently selected at each occurrence from hydrogen, -F, or methyl.

在一些實施方式中，p選自0、1、2或3。In some embodiments, p is selected from 0, 1, 2 or 3.

在一些實施方式中，p選自0、1或2。In some embodiments, p is selected from 0, 1 or 2.

在一些實施方式中，p選自0或1。In some embodiments, p is selected from 0 or 1.

在一些實施方式中，p選自0。In some embodiments, p is selected from zero.

在一些實施方式中，p選自1。In some embodiments, p is selected from 1 .

在一些實施方式中，q選自0、1、2或3。In some embodiments, q is selected from 0, 1, 2, or 3.

在一些實施方式中，q選自0、1或2。In some embodiments, q is selected from 0, 1 or 2.

在一些實施方式中，q選自0或1。In some embodiments, q is selected from 0 or 1.

在一些實施方式中，q選自0。In some embodiments, q is selected from zero.

在一些實施方式中，q選自1。In some embodiments, q is selected from 1.

在一些實施方式中，每個R7 在每次出現時獨立地選自-F、-Cl、-Br、-C1-3 烷基、-C1-3 亞烷基-(鹵素)1-3 、C1-3 雜烷基、-C2-3 烯基、-C2-3 炔基、氧代、-OR8 、-C1-3 亞烷基-(OR8 )1-3 、-O-C1-3 亞烷基-(鹵素)1-3 、-NR8 R9 、-C1-3 亞烷基-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 、-C6 -10 芳基、5-10元雜芳基、3-6元雜環基或-C3-6 碳環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O或S的雜原子；每個R7 在每次出現時獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、氧代、-C1-3 烷基、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 或-S(O)2 NR8 R9 的取代基取代； 每個R7 中的R8 和R9 在每次出現時獨立地選自氫或-C1-3 烷基；或 R7 中的R8 和R9 與它們共同連接的N原子一起形成3-6元雜環，所述的3-6元雜環可進一步包含1、2、3或4個選自N、O或S的雜原子。In some embodiments, each R 7 is independently selected at each occurrence from -F, -Cl, -Br, -C 1-3 alkyl, -C 1-3 alkylene-(halogen) 1- 3 , C 1-3 heteroalkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, oxo, -OR 8 , -C 1-3 alkylene-(OR 8 ) 1-3 , -OC 1-3 alkylene-(halogen) 1-3 , -NR 8 R 9 , -C 1-3 alkylene-NR 8 R 9 , -CN, -C(=O)R 8 , -C (=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 , - C 6 - 10 aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl or -C 3-6 carbocyclic group, a heterocyclic group, and each heteroaryl is independently at each occurrence 1 comprising 2, 3 or 4 heteroatoms selected from N, O or S heteroatom; each R 7 is independently at each occurrence, optionally 5 or 6 is selected from -F, -Cl, -Br, oxo, -C 1-3 alkyl, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC Substituent substitution of (=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 or -S(O) 2 NR 8 R 9 ; in each R 7 R 8 and R 9 at each occurrence are independently selected from hydrogen or -C 1-3 alkyl; or R 8 and R 9 in R 7 together with the N atom to which they are commonly attached form a 3-6 membered heterocycle, The 3-6 membered heterocycle may further comprise 1, 2, 3 or 4 heteroatoms selected from N, O or S.

在一些實施方式中，每個R7 在每次出現時獨立地選自-F、-Cl、-Br、甲基、乙基、丙基、異丙基、-亞甲基-(鹵素)1-3 、-亞乙基-(鹵素)1-3 、-亞丙基-(鹵素)1-3 、雜甲基、雜乙基、雜丙基、乙烯基、丙烯基、乙炔基、丙炔基、氧代、-OR8 、-亞甲基-(OR8 )1-3 、-亞乙基-(OR8 )1-3 、-亞丙基-(OR8 )1-3 、-O-亞甲基-(鹵素)1-3 、-O-亞乙基-(鹵素)1-3 、-O-亞丙基-(鹵素)1-3 、-NR8 R9 、-亞甲基-NR8 R9 、-亞乙基-NR8 R9 、-亞丙基-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、-S(O)2 NR8 R9 、苯基、萘基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基、10元雜芳基、3元雜環基、4元雜環基、5元雜環基、6元雜環基、3元碳環基、4元碳環基、5元碳環基或6元碳環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O或S的雜原子；每個R7 在每次出現時獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 的取代基取代； 每個R7 中的R8 和R9 在每次出現時獨立地選自氫、甲基、乙基、丙基或異丙基；或 R7 中的R8 和R9 與它們共同連接的N原子一起形成

Figure 02_image377
、
Figure 02_image379
或
Figure 02_image381
。In some embodiments, each R 7 at each occurrence is independently selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, - methylene - (halo) 1 -3 , -ethylene-(halogen) 1-3 , -propylene-(halogen) 1-3 , heteromethyl, heteroethyl, heteropropyl, vinyl, propenyl, ethynyl, propyne , oxo, -OR 8, - methylene - (OR 8) 1-3, - ethylidene - (OR 8) 1-3, - propylene - (OR 8) 1-3, -O -methylene-(halogen) 1-3 , -O-ethylene-(halogen) 1-3 , -O-propylene-(halogen) 1-3 , -NR 8 R 9 , -methylene -NR 8 R 9 , -ethylene-NR 8 R 9 , -propylene-NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC( =O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 , phenyl, naphthyl, 5-membered heteroaryl , 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl, each heterocyclyl and heteroaryl independently containing at each occurrence 1, 2, 3 or 4 heteroatoms selected from N, O or S heteroatom; each R 7 is independently at each occurrence, optionally 5 or 6 is selected from -F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , Substituent substitution of -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 ; each R the 7 R 8 and R 9 at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; or R R 78 in R 9 together with the N atom to which they are attached form
Figure 02_image377
,
Figure 02_image379
or
Figure 02_image381
.

在一些實施方式中，每個R7 在每次出現時獨立地選自-F、-Cl、-Br、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、乙烯基、丙烯基、乙炔基、丙炔基、氧代、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CH2 F、-OCH2 CHF2 、-OCH2 CF3 、-OCH2 CH2 CH2 F、-OCH2 CH2 CHF2 、-OCH2 CH2 CF3 、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、

Figure 02_image457
、
Figure 02_image459
or
Figure 02_image461
、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 N(CH3 )2 、苯基、萘基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基、10元雜芳基、3元碳環基、4元碳環基、5元碳環基或6元碳環基；每個R7 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、-OH、-NH2 、-N(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 取代基的取代或不取代。In some embodiments, each R 7 at each occurrence is independently selected from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2, -CF 3, -CH 2 CH 2 F , -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , vinyl, propenyl, ethynyl, propynyl, oxo, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 CH 2 F, -OCH 2 CH 2 CHF 2 , -OCH 2 CH 2 CF 3 , -NH 2 , - NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 3 , -N(CH 3 ) CH 2 CH 2 CH 3, -N (CH 3) CH (CH 3) 2, -CH 2 NH 2, -CH 2 CH 2 NH 2, -CH 2 CH 2 CH 2 NH 2, -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CN, -C(=O)CH 3 , -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH (CH 3 ), -C(=O)N(CH 3 ) 2 ,
Figure 02_image457
,
Figure 02_image459
or
Figure 02_image461
, -NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N(CH 3 ) 2 , phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 3 yuan carbocyclyl 4 membered carbocyclic 5-membered carbocyclic group or a 6-membered carbocyclic group; each R 7 is independently optionally substituted 5 or 6 selected from -F , -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -OH, -NH 2 , -N( CH 3 ) 2 , -CN, -C(=O)CH 3 , -C(=O)OCH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O) NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ) or -S(O) 2 N(CH 3 ) 2 substituents are substituted or unsubstituted.

在一些實施方式中，每個R7 在每次出現時獨立地選自-F、-CH3 、-CH2 CH2 OCH3 、-CF3 、-OCF3 、-CN、

Figure 02_image463
、-C(=O)OCH2 CH3 、-C(=O)N(CH3 )2 、
Figure 02_image465
、-C(O)NHCH3 、-NHC(=O)CH3 或-S(=O)2 N(CH3 )2 。In some embodiments, each R 7 at each occurrence is independently selected from -F, -CH 3, -CH 2 CH 2 OCH 3, -CF 3, -OCF 3, -CN,
Figure 02_image463
, -C(=O)OCH 2 CH 3 , -C(=O)N(CH 3 ) 2 ,
Figure 02_image465
, -C(O)NHCH 3 , -NHC(=O)CH 3 or -S(=O) 2 N(CH 3 ) 2 .

在一些實施方式中，

Figure 02_image467
選自：
Figure 02_image469
、
Figure 02_image471
、
Figure 02_image473
、
Figure 02_image475
、
Figure 02_image477
、
Figure 02_image479
、
Figure 02_image481
、
Figure 02_image483
、
Figure 02_image485
、
Figure 02_image487
、
Figure 02_image489
、
Figure 02_image491
、
Figure 02_image493
、
Figure 02_image495
、
Figure 02_image497
、
Figure 02_image499
、
Figure 02_image501
、
Figure 02_image503
、
Figure 02_image505
、
Figure 02_image507
、
Figure 02_image509
、
Figure 02_image511
、
Figure 02_image513
、
Figure 02_image515
、
Figure 02_image517
、
Figure 02_image519
、
Figure 02_image521
、
Figure 02_image523
、
Figure 02_image525
、
Figure 02_image527
、
Figure 02_image529
、
Figure 02_image531
、
Figure 02_image533
、
Figure 02_image535
、
Figure 02_image537
、
Figure 02_image539
、
Figure 02_image541
、
Figure 02_image543
、
Figure 02_image545
、
Figure 02_image547
、
Figure 02_image549
、
Figure 02_image551
、
Figure 02_image553
、
Figure 02_image555
、
Figure 02_image557
、
Figure 02_image559
、
Figure 02_image561
、
Figure 02_image563
、
Figure 02_image565
、
Figure 02_image567
、
Figure 02_image569
、
Figure 02_image571
、
Figure 02_image573
、
Figure 02_image575
、
Figure 02_image577
、
Figure 02_image579
、
Figure 02_image581
、
Figure 02_image583
、
Figure 02_image585
、
Figure 02_image587
、
Figure 02_image589
、
Figure 02_image591
、
Figure 02_image593
、
Figure 02_image595
、
Figure 02_image597
、
Figure 02_image599
、
Figure 02_image601
、
Figure 02_image603
、
Figure 02_image605
、
Figure 02_image607
、
Figure 02_image609
、
Figure 02_image469
、
Figure 02_image471
、
Figure 02_image473
、
Figure 02_image475
、
Figure 02_image477
、
Figure 02_image479
、
Figure 02_image481
、
Figure 02_image483
、
Figure 02_image485
、
Figure 02_image487
、
Figure 02_image489
、
Figure 02_image491
、
Figure 02_image493
、
Figure 02_image495
、
Figure 02_image497
、
Figure 02_image499
、
Figure 02_image501
、
Figure 02_image503
、
Figure 02_image505
、
Figure 02_image507
、
Figure 02_image509
、
Figure 02_image511
、
Figure 02_image513
、
Figure 02_image515
、
Figure 02_image517
、
Figure 02_image519
、
Figure 02_image521
、
Figure 02_image523
、
Figure 02_image525
、
Figure 02_image527
、
Figure 02_image529
、
Figure 02_image531
、
Figure 02_image533
、
Figure 02_image535
、
Figure 02_image537
、
Figure 02_image539
、
Figure 02_image541
、
Figure 02_image543
、
Figure 02_image545
、
Figure 02_image547
、
Figure 02_image549
、
Figure 02_image551
、
Figure 02_image553
、
Figure 02_image555
、
Figure 02_image557
、
Figure 02_image559
、
Figure 02_image561
、
Figure 02_image563
、
Figure 02_image565
、
Figure 02_image567
、
Figure 02_image569
、
Figure 02_image571
、
Figure 02_image573
、
Figure 02_image575
、
Figure 02_image577
、
Figure 02_image579
、
Figure 02_image581
、
Figure 02_image583
、
Figure 02_image585
、
Figure 02_image587
、
Figure 02_image589
、
Figure 02_image591
、
Figure 02_image593
、
Figure 02_image595
、
Figure 02_image597
、
Figure 02_image599
、
Figure 02_image601
、
Figure 02_image603
、
Figure 02_image605
、
Figure 02_image607
、
Figure 02_image609
、
Figure 02_image681
、
Figure 02_image683
、
Figure 02_image685
、
Figure 02_image687
、
Figure 02_image689
、
Figure 02_image691
、
Figure 02_image693
、
Figure 02_image695
、
Figure 02_image697
、
Figure 02_image699
、
Figure 02_image701
、
Figure 02_image703
、
Figure 02_image705
、
Figure 02_image707
、
Figure 02_image709
、
Figure 02_image711
、
Figure 02_image713
、
Figure 02_image715
、
Figure 02_image717
、
Figure 02_image719
、
Figure 02_image721
、
Figure 02_image723
、
Figure 02_image725
、
Figure 02_image727
、
Figure 02_image729
、
Figure 02_image731
、
Figure 02_image733
、
Figure 02_image735
、
Figure 02_image737
、
Figure 02_image739
、
Figure 02_image741
、
Figure 02_image743
或
Figure 02_image745
。In some embodiments,
Figure 02_image467
Selected from:
Figure 02_image469
,
Figure 02_image471
,
Figure 02_image473
,
Figure 02_image475
,
Figure 02_image477
,
Figure 02_image479
,
Figure 02_image481
,
Figure 02_image483
,
Figure 02_image485
,
Figure 02_image487
,
Figure 02_image489
,
Figure 02_image491
,
Figure 02_image493
,
Figure 02_image495
,
Figure 02_image497
,
Figure 02_image499
,
Figure 02_image501
,
Figure 02_image503
,
Figure 02_image505
,
Figure 02_image507
,
Figure 02_image509
,
Figure 02_image511
,
Figure 02_image513
,
Figure 02_image515
,
Figure 02_image517
,
Figure 02_image519
,
Figure 02_image521
,
Figure 02_image523
,
Figure 02_image525
,
Figure 02_image527
,
Figure 02_image529
,
Figure 02_image531
,
Figure 02_image533
,
Figure 02_image535
,
Figure 02_image537
,
Figure 02_image539
,
Figure 02_image541
,
Figure 02_image543
,
Figure 02_image545
,
Figure 02_image547
,
Figure 02_image549
,
Figure 02_image551
,
Figure 02_image553
,
Figure 02_image555
,
Figure 02_image557
,
Figure 02_image559
,
Figure 02_image561
,
Figure 02_image563
,
Figure 02_image565
,
Figure 02_image567
,
Figure 02_image569
,
Figure 02_image571
,
Figure 02_image573
,
Figure 02_image575
,
Figure 02_image577
,
Figure 02_image579
,
Figure 02_image581
,
Figure 02_image583
,
Figure 02_image585
,
Figure 02_image587
,
Figure 02_image589
,
Figure 02_image591
,
Figure 02_image593
,
Figure 02_image595
,
Figure 02_image597
,
Figure 02_image599
,
Figure 02_image601
,
Figure 02_image603
,
Figure 02_image605
,
Figure 02_image607
,
Figure 02_image609
,
Figure 02_image469
,
Figure 02_image471
,
Figure 02_image473
,
Figure 02_image475
,
Figure 02_image477
,
Figure 02_image479
,
Figure 02_image481
,
Figure 02_image483
,
Figure 02_image485
,
Figure 02_image487
,
Figure 02_image489
,
Figure 02_image491
,
Figure 02_image493
,
Figure 02_image495
,
Figure 02_image497
,
Figure 02_image499
,
Figure 02_image501
,
Figure 02_image503
,
Figure 02_image505
,
Figure 02_image507
,
Figure 02_image509
,
Figure 02_image511
,
Figure 02_image513
,
Figure 02_image515
,
Figure 02_image517
,
Figure 02_image519
,
Figure 02_image521
,
Figure 02_image523
,
Figure 02_image525
,
Figure 02_image527
,
Figure 02_image529
,
Figure 02_image531
,
Figure 02_image533
,
Figure 02_image535
,
Figure 02_image537
,
Figure 02_image539
,
Figure 02_image541
,
Figure 02_image543
,
Figure 02_image545
,
Figure 02_image547
,
Figure 02_image549
,
Figure 02_image551
,
Figure 02_image553
,
Figure 02_image555
,
Figure 02_image557
,
Figure 02_image559
,
Figure 02_image561
,
Figure 02_image563
,
Figure 02_image565
,
Figure 02_image567
,
Figure 02_image569
,
Figure 02_image571
,
Figure 02_image573
,
Figure 02_image575
,
Figure 02_image577
,
Figure 02_image579
,
Figure 02_image581
,
Figure 02_image583
,
Figure 02_image585
,
Figure 02_image587
,
Figure 02_image589
,
Figure 02_image591
,
Figure 02_image593
,
Figure 02_image595
,
Figure 02_image597
,
Figure 02_image599
,
Figure 02_image601
,
Figure 02_image603
,
Figure 02_image605
,
Figure 02_image607
,
Figure 02_image609
,
Figure 02_image681
,
Figure 02_image683
,
Figure 02_image685
,
Figure 02_image687
,
Figure 02_image689
,
Figure 02_image691
,
Figure 02_image693
,
Figure 02_image695
,
Figure 02_image697
,
Figure 02_image699
,
Figure 02_image701
,
Figure 02_image703
,
Figure 02_image705
,
Figure 02_image707
,
Figure 02_image709
,
Figure 02_image711
,
Figure 02_image713
,
Figure 02_image715
,
Figure 02_image717
,
Figure 02_image719
,
Figure 02_image721
,
Figure 02_image723
,
Figure 02_image725
,
Figure 02_image727
,
Figure 02_image729
,
Figure 02_image731
,
Figure 02_image733
,
Figure 02_image735
,
Figure 02_image737
,
Figure 02_image739
,
Figure 02_image741
,
Figure 02_image743
or
Figure 02_image745
.

在一些實施方式中，

Figure 02_image747
選自：
Figure 02_image749
、
Figure 02_image751
、
Figure 02_image753
、
Figure 02_image755
、
Figure 02_image757
、
Figure 02_image759
、
Figure 02_image761
、
Figure 02_image763
、
Figure 02_image765
、
Figure 02_image767
、
Figure 02_image769
、
Figure 02_image771
、
Figure 02_image773
、
Figure 02_image775
、
Figure 02_image777
、
Figure 02_image779
、
Figure 02_image781
、
Figure 02_image783
、
Figure 02_image785
、
Figure 02_image787
、
Figure 02_image789
、
Figure 02_image791
、
Figure 02_image793
、
Figure 02_image795
、
Figure 02_image797
、
Figure 02_image799
、
Figure 02_image801
、
Figure 02_image803
、
Figure 02_image805
、
Figure 02_image807
、
Figure 02_image809
、
Figure 02_image811
、
Figure 02_image813
、
Figure 02_image815
、
Figure 02_image817
、
Figure 02_image819
、
Figure 02_image821
、
Figure 02_image823
、
Figure 02_image825
、
Figure 02_image827
、
Figure 02_image829
、
Figure 02_image831
、
Figure 02_image833
、
Figure 02_image835
、
Figure 02_image837
、
Figure 02_image839
、
Figure 02_image841
、
Figure 02_image843
、
Figure 02_image845
、
Figure 02_image847
、
Figure 02_image849
、
Figure 02_image851
、
Figure 02_image853
、
Figure 02_image855
、
Figure 02_image857
、
Figure 02_image859
、
Figure 02_image861
、
Figure 02_image863
、
Figure 02_image865
、
Figure 02_image867
、
Figure 02_image869
、
Figure 02_image871
、
Figure 02_image873
、
Figure 02_image875
、
Figure 02_image877
、
Figure 02_image879
、
Figure 02_image881
、
Figure 02_image883
、
Figure 02_image885
、
Figure 02_image887
、
Figure 02_image889
、
Figure 02_image891
、
Figure 02_image749
、
Figure 02_image751
、
Figure 02_image753
、
Figure 02_image755
、
Figure 02_image757
、
Figure 02_image759
、
Figure 02_image761
、
Figure 02_image763
、
Figure 02_image765
、
Figure 02_image767
、
Figure 02_image769
、
Figure 02_image771
、
Figure 02_image773
、
Figure 02_image775
、
Figure 02_image777
、
Figure 02_image779
、
Figure 02_image781
、
Figure 02_image783
、
Figure 02_image785
、
Figure 02_image787
、
Figure 02_image789
、
Figure 02_image791
、
Figure 02_image793
、
Figure 02_image795
、
Figure 02_image797
、
Figure 02_image799
、
Figure 02_image801
、
Figure 02_image803
、
Figure 02_image805
、
Figure 02_image807
、
Figure 02_image809
、
Figure 02_image811
、
Figure 02_image813
、
Figure 02_image815
、
Figure 02_image817
、
Figure 02_image819
、
Figure 02_image821
、
Figure 02_image823
、
Figure 02_image825
、
Figure 02_image827
、
Figure 02_image829
、
Figure 02_image831
、
Figure 02_image833
、
Figure 02_image835
、
Figure 02_image837
、
Figure 02_image839
、
Figure 02_image841
、
Figure 02_image843
、
Figure 02_image845
、
Figure 02_image847
、
Figure 02_image849
、
Figure 02_image851
、
Figure 02_image853
、
Figure 02_image855
、
Figure 02_image857
、
Figure 02_image859
、
Figure 02_image861
、
Figure 02_image863
、
Figure 02_image865
、
Figure 02_image867
、
Figure 02_image869
、
Figure 02_image871
、
Figure 02_image873
、
Figure 02_image875
、
Figure 02_image877
、
Figure 02_image879
、
Figure 02_image881
、
Figure 02_image883
、
Figure 02_image885
、
Figure 02_image887
、
Figure 02_image889
、
Figure 02_image891
、
Figure 02_image957
、
Figure 02_image959
、
Figure 02_image961
、
Figure 02_image963
、
Figure 02_image965
、
Figure 02_image967
、
Figure 02_image969
、
Figure 02_image971
、
Figure 02_image973
、
Figure 02_image975
、
Figure 02_image977
、
Figure 02_image979
、
Figure 02_image981
、
Figure 02_image983
、
Figure 02_image985
、
Figure 02_image987
、
Figure 02_image989
、
Figure 02_image991
、
Figure 02_image993
、
Figure 02_image995
、
Figure 02_image997
、
Figure 02_image999
、
Figure 02_image1001
、
Figure 02_image1003
、
Figure 02_image1005
、
Figure 02_image1007
、
Figure 02_image1009
、
Figure 02_image1011
、
Figure 02_image1013
、
Figure 02_image1015
、
Figure 02_image1017
、
Figure 02_image1019
或
Figure 02_image1021
。In some embodiments,
Figure 02_image747
Selected from:
Figure 02_image749
,
Figure 02_image751
,
Figure 02_image753
,
Figure 02_image755
,
Figure 02_image757
,
Figure 02_image759
,
Figure 02_image761
,
Figure 02_image763
,
Figure 02_image765
,
Figure 02_image767
,
Figure 02_image769
,
Figure 02_image771
,
Figure 02_image773
,
Figure 02_image775
,
Figure 02_image777
,
Figure 02_image779
,
Figure 02_image781
,
Figure 02_image783
,
Figure 02_image785
,
Figure 02_image787
,
Figure 02_image789
,
Figure 02_image791
,
Figure 02_image793
,
Figure 02_image795
,
Figure 02_image797
,
Figure 02_image799
,
Figure 02_image801
,
Figure 02_image803
,
Figure 02_image805
,
Figure 02_image807
,
Figure 02_image809
,
Figure 02_image811
,
Figure 02_image813
,
Figure 02_image815
,
Figure 02_image817
,
Figure 02_image819
,
Figure 02_image821
,
Figure 02_image823
,
Figure 02_image825
,
Figure 02_image827
,
Figure 02_image829
,
Figure 02_image831
,
Figure 02_image833
,
Figure 02_image835
,
Figure 02_image837
,
Figure 02_image839
,
Figure 02_image841
,
Figure 02_image843
,
Figure 02_image845
,
Figure 02_image847
,
Figure 02_image849
,
Figure 02_image851
,
Figure 02_image853
,
Figure 02_image855
,
Figure 02_image857
,
Figure 02_image859
,
Figure 02_image861
,
Figure 02_image863
,
Figure 02_image865
,
Figure 02_image867
,
Figure 02_image869
,
Figure 02_image871
,
Figure 02_image873
,
Figure 02_image875
,
Figure 02_image877
,
Figure 02_image879
,
Figure 02_image881
,
Figure 02_image883
,
Figure 02_image885
,
Figure 02_image887
,
Figure 02_image889
,
Figure 02_image891
,
Figure 02_image749
,
Figure 02_image751
,
Figure 02_image753
,
Figure 02_image755
,
Figure 02_image757
,
Figure 02_image759
,
Figure 02_image761
,
Figure 02_image763
,
Figure 02_image765
,
Figure 02_image767
,
Figure 02_image769
,
Figure 02_image771
,
Figure 02_image773
,
Figure 02_image775
,
Figure 02_image777
,
Figure 02_image779
,
Figure 02_image781
,
Figure 02_image783
,
Figure 02_image785
,
Figure 02_image787
,
Figure 02_image789
,
Figure 02_image791
,
Figure 02_image793
,
Figure 02_image795
,
Figure 02_image797
,
Figure 02_image799
,
Figure 02_image801
,
Figure 02_image803
,
Figure 02_image805
,
Figure 02_image807
,
Figure 02_image809
,
Figure 02_image811
,
Figure 02_image813
,
Figure 02_image815
,
Figure 02_image817
,
Figure 02_image819
,
Figure 02_image821
,
Figure 02_image823
,
Figure 02_image825
,
Figure 02_image827
,
Figure 02_image829
,
Figure 02_image831
,
Figure 02_image833
,
Figure 02_image835
,
Figure 02_image837
,
Figure 02_image839
,
Figure 02_image841
,
Figure 02_image843
,
Figure 02_image845
,
Figure 02_image847
,
Figure 02_image849
,
Figure 02_image851
,
Figure 02_image853
,
Figure 02_image855
,
Figure 02_image857
,
Figure 02_image859
,
Figure 02_image861
,
Figure 02_image863
,
Figure 02_image865
,
Figure 02_image867
,
Figure 02_image869
,
Figure 02_image871
,
Figure 02_image873
,
Figure 02_image875
,
Figure 02_image877
,
Figure 02_image879
,
Figure 02_image881
,
Figure 02_image883
,
Figure 02_image885
,
Figure 02_image887
,
Figure 02_image889
,
Figure 02_image891
,
Figure 02_image957
,
Figure 02_image959
,
Figure 02_image961
,
Figure 02_image963
,
Figure 02_image965
,
Figure 02_image967
,
Figure 02_image969
,
Figure 02_image971
,
Figure 02_image973
,
Figure 02_image975
,
Figure 02_image977
,
Figure 02_image979
,
Figure 02_image981
,
Figure 02_image983
,
Figure 02_image985
,
Figure 02_image987
,
Figure 02_image989
,
Figure 02_image991
,
Figure 02_image993
,
Figure 02_image995
,
Figure 02_image997
,
Figure 02_image999
,
Figure 02_image1001
,
Figure 02_image1003
,
Figure 02_image1005
,
Figure 02_image1007
,
Figure 02_image1009
,
Figure 02_image1011
,
Figure 02_image1013
,
Figure 02_image1015
,
Figure 02_image1017
,
Figure 02_image1019
or
Figure 02_image1021
.

在一些實施方式中，每個L4 在每次出現時獨立地選自不存在或(CR5 R6 )m 。In some embodiments, each of L 4 at each occurrence is independently absent or selected from (CR 5 R 6) m.

在一些實施方式中，每個L4 在每次出現時獨立地選自不存在。In some embodiments, each of L 4 at each occurrence is independently selected from absent.

在一些實施方式中，每個R4 在每次出現時獨立地選自

Figure 02_image014
、
Figure 02_image016
或
Figure 02_image018
，每個R4 在每次出現時獨立地可選地被1、2、3、4、5或6個R42 取代或不取代。In some embodiments, each R 4 is independently at each occurrence selected from
Figure 02_image014
,
Figure 02_image016
or
Figure 02_image018
Each R 4 is independently optionally substituted 5 or 6 unsubstituted or substituted with R 42 at each occurrence.

在一些實施方式中，每個R4 在每次出現時獨立地選自

Figure 02_image014
，每個R4 在每次出現時獨立地可選地被1、2、3、4、5或6個R42 取代或不被取代。In some embodiments, each R 4 is independently at each occurrence selected from
Figure 02_image014
Each R 4 is independently optionally substituted 5 or 6 or R 42 substituent is not substituted at each occurrence.

在一些實施方式中，每個G1 和G2 在每次出現時獨立地選自N。In some embodiments, each G 1 and G 2 are independently at each occurrence selected from N.

在一些實施方式中，每個n1和n2在每次出現時獨立地選自1、2或3。In some embodiments, each of n1 and n2 is independently selected from 1, 2, or 3 at each occurrence.

在一些實施方式中，每個R4 在每次出現時獨立地選自

Figure 02_image1027
；每個R4 在每次出現時獨立地可選地被1、2、3、4、5或6個R42 取代或不被取代。In some embodiments, each R 4 is independently at each occurrence selected from
Figure 02_image1027
; Each R 4 is independently optionally substituted 5 or 6 or R 42 substituent is not substituted at each occurrence.

在一些實施方式中，每個R4 在每次出現時獨立地選自

Figure 02_image1027
；每個R4 在每次出現時獨立地可選地被1、2、3、4、5或6個R42 取代或不取代，且L4 選自不存在。In some embodiments, each R 4 is independently at each occurrence selected from
Figure 02_image1027
; Each R 4 is independently in each occurrence optionally be 5 or 6 R 42 substituted or unsubstituted, and L 4 is selected from absent.

在一些實施方式中，每個R41 在每次出現時獨立地選自

Figure 02_image022
； 每個Q在每次出現時獨立地選自C(=O)或S(=O)2 。In some embodiments, each R 41 is independently selected at each occurrence
Figure 02_image022
; each Q is independently selected at each occurrence from C(=O) or S(=O) 2 .

在一些實施方式中，每個R41 在每次出現時獨立地選自

Figure 02_image022
； 每個Q在每次出現時獨立地選自或C(=O)。In some embodiments, each R 41 is independently selected at each occurrence
Figure 02_image022
; each Q is independently selected at each occurrence from or C (=O).

在一些實施方式中，當

Figure 02_image024
選自
Figure 02_image026
時，每個R4a 、R4b 和R4c 在每次出現時獨立地選自氫、-F、-Cl、-Br、氧代、-C1-3 烷基、-C1-3 亞烷基-(鹵素)1-3 、C1-3 雜烷基、-CN、-OR8 、-C1-3 亞烷基-(OR8 )1-3 、-NR8 R9 、-C1-3 亞烷基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-C1-3 亞烷基-C(=O)NR8 R9 、-NR8 C(=O)R8 、-C1-3 亞烷基-NR8 C(=O)R8 、-S(O)2 NR8 R9 或-C3-6 碳環基；每個R4a 、R4b 或R4c 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、-C1-3 烷基、-C1-3 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 ,或-S(O)2 NR8 R9 的取代基取代或不取代；或R4b 和R4c 與它們共同連接的碳原子形成選自C3-6 碳環或3-6元雜環，每個3-6元雜環在每次出現時包含1、2或3個選自N、O或S的雜原子，且每個C3-6 碳環或3-6元雜環基可選地可以被1、2、3、4、5或6個選自-F、-Cl、-Br、-C1-3 烷基、-C1-3 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 ,或-S(O)2 NR8 R9 的取代基取代或不取代； 當
Figure 02_image024
選自
Figure 02_image028
時，每個R4a 是不存在，且R4b 和R4c 中之一選自不存在，R4b 和R4c 中的另外一個選自氫、-F、-Cl、-Br、氧代、-C1-3 烷基、-C1-3 亞烷基-(鹵素)1-3 、C1-3 雜烷基、-CN、-OR8 、-C1-3 亞烷基-(OR8 )1-3 、-NR8 R9 、-C1-3 亞烷基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-C1-3 亞烷基-C(=O)NR8 R9 、-NR8 C(=O)R8 、-C1-3 亞烷基-NR8 C(=O)R8 、-S(O)2 NR8 R9 或-C3-6 碳環基；每個R4b 或R4c 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、-C1-3 烷基、-C1-3 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 ,或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R4a 、R4b 或R4c 中的R8 和R9 在每次出現時獨立地選自氫或-C1 -3 烷基，或 R4a 、R4b 或R4c 中的R8 和R9 與它們共同連接的N原子一起形成3-6元雜環，所述的3-6元雜環可進一步包含1、2、3或4個選自N、O或S的雜原子。In some embodiments, when
Figure 02_image024
selected from
Figure 02_image026
, each R 4a , R 4b and R 4c at each occurrence is independently selected from hydrogen, -F, -Cl, -Br, oxo, -C 1-3 alkyl, -C 1-3 alkylene Base-(halogen) 1-3 , C 1-3 heteroalkyl, -CN, -OR 8 , -C 1-3 alkylene-(OR 8 ) 1-3 , -NR 8 R 9 , -C 1 -3 alkylene -NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , - C 1-3 alkylene-C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -C 1-3 alkylene-NR 8 C(=O)R 8 , -S (O) 2 NR 8 R 9 or -C 3-6 carbocyclyl; each R 4a , R 4b or R 4c is independently optionally selected from -F by 1, 2, 3, 4, 5 or 6 , -Cl, -Br, -C 1-3 alkyl, -C 1-3 alkoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , - C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 The substituents are substituted or unsubstituted; or R 4b and R 4c and the carbon atoms to which they are commonly attached form a C 3-6 carbocyclic ring or a 3-6 membered heterocycle, each 3-6 membered heterocycle at each occurrence contains 1, 2 or 3 heteroatoms selected from N, O or S, and each C 3-6 carbocyclic or 3-6 membered heterocyclic group may optionally be replaced by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, -Br, -C 1-3 alkyl, -C 1-3 alkoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C ( =O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S( O) Substituents of 2 NR 8 R 9 are substituted or unsubstituted; when
Figure 02_image024
selected from
Figure 02_image028
When each R 4a is absent, and one of R 4b and R 4c is selected from absent, and the other of R 4b and R 4c is selected from hydrogen, -F, -Cl, -Br, oxo, - C 1-3 alkyl, -C 1-3 alkylene-(halogen) 1-3 , C 1-3 heteroalkyl, -CN, -OR 8 , -C 1-3 alkylene-(OR 8 ) 1-3 , -NR 8 R 9 , -C 1-3 alkylene -NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -C 1-3 alkylene -C(=O)NR 8 R 9 , -NR 8 C(=O) R 8 , -C 1-3 alkylene A radical -NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 or -C 3-6 carbocyclyl; each R 4b or R 4c is independently optionally replaced by 1, 2, 3 , 4, 5 or 6 are selected from -F, -Cl, -Br, -C 1-3 alkyl, -C 1-3 alkoxy, oxo, -OR 8 , -NR 8 R 9 , -CN , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 substituents substituted or unsubstituted; R 8 and R 9 in each R 4a , R 4b or R 4c are independently selected at each occurrence from hydrogen or -C 1 - 3- alkyl, or R 8 and R 9 in R 4a , R 4b or R 4c together with the N atom to which they are connected together form a 3-6 membered heterocycle, and the 3-6 membered heterocycle may further comprise 1 , 2, 3 or 4 heteroatoms selected from N, O or S.

在一些實施方式中，當

Figure 02_image024
選自
Figure 02_image026
時，每個R4a 、R4b 和R4c 在每次出現時獨立地選自氫、-F、-Cl、氧代、甲基、乙基、丙基、異丙基、-亞甲基-(鹵素)1-3 、-亞乙基-(鹵素)1-3 、-亞丙基-(鹵素)1-3 、雜乙基、雜丙基、-CN、-OR8 、-亞甲基-(OR8 )1-3 、-亞乙基-(OR8 )1-3 、-亞丙基-(OR8 )1-3 、-NR8 R9 、-亞甲基-NR8 R9 、-亞乙基-NR8 R9 、-亞丙基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-亞甲基-C(=O)NR8 R9 、-亞乙基-C(=O)NR8 R9 、-亞丙基-C(=O)NR8 R9 、-NR8 C(=O)R8 、-亞甲基-NR8 C(=O)R8 、-亞乙基-NR8 C(=O)R8 、-亞丙基-NR8 C(=O)R8 、-S(O)2 NR8 R9 、3元碳環基、4元碳環基、5元碳環基或6元碳環基；每個R4a 、R4b 或R4c 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 ,或-S(O)2 NR8 R9 的取代基取代或不取代；或R4b 和R4c 與它們共同連接的碳原子形成選自3元碳環、4元碳環、5元碳環、6元碳環、3元雜環、4元雜環、5元雜環或6元雜環的環，每個3-6元雜環在每次出現時包含1或2個選自N或O的雜原子，且每個3-6元碳環或3-6元雜環可選地可以被1、2、3、4、5或6個選自-F、-Cl、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 或-S(O)2 NR8 R9 的取代基取代或不取代； 當
Figure 02_image024
選自
Figure 02_image028
時，每個R4a 是不存在，且R4b 和R4c 中之一是不存在，R4b 和R4c 中的另一個選自氫、-F、-Cl、氧代、甲基、乙基、丙基、異丙基、-亞甲基-(鹵素)1-3 、-亞乙基-(鹵素)1-3 、-亞丙基-(鹵素)1-3 、雜乙基、雜丙基、-CN、-OR8 、-亞甲基-(OR8 )1-3 、-亞乙基-(OR8 )1-3 、-亞丙基-(OR8 )1-3 、-NR8 R9 、-亞甲基-NR8 R9 、-亞乙基-NR8 R9 、-亞丙基-NR8 R9 、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-亞甲基-C(=O)NR8 R9 、-亞乙基-C(=O)NR8 R9 、-亞丙基-C(=O)NR8 R9 、-NR8 C(=O)R8 、-亞甲基-NR8 C(=O)R8 、-亞乙基-NR8 C(=O)R8 、-亞丙基-NR8 C(=O)R8 、-S(O)2 NR8 R9 、3元碳環基、4元碳環基、5元碳環基或6元碳環基；每個R4b 或R4c 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R4a 、R4b 或R4c 中的R8 和R9 在每次出現時獨立地選自氫、甲基、乙基、丙基或異丙基；或 R4a 、R4b 或R4c 中的R8 和R9 與它們共同連接的N原子一起形成
Figure 02_image377
、
Figure 02_image379
或
Figure 02_image381
。In some embodiments, when
Figure 02_image024
selected from
Figure 02_image026
, each R 4a , R 4b and R 4c at each occurrence is independently selected from hydrogen, -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -methylene- (halogen) 1-3 , -ethylene-(halogen) 1-3 , -propylene-(halogen) 1-3 , heteroethyl, heteropropyl, -CN, -OR 8 , -methylene -(OR 8 ) 1-3 , -ethylene-(OR 8 ) 1-3 , -propylene-(OR 8 ) 1-3 , -NR 8 R 9 , -methylene-NR 8 R 9 , -ethylene-NR 8 R 9 , -propylene-NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C (=O)NR 8 R 9 , -methylene-C(=O)NR 8 R 9 , -ethylene-C(=O)NR 8 R 9 , -propylene-C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -methylene-NR 8 C(=O)R 8 , -ethylene-NR 8 C(=O)R 8 , -propylene- NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; each R 4a , R 4b or R 4c is independently optionally replaced by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy group, propoxy, isopropoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O ) R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 is substituted or unsubstituted with a substituent; or R 4b and R 4c and the carbon atoms to which they are commonly attached form a carbocycle selected from the group consisting of 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, 6-membered carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, or 6-membered heterocycle ring, each 3-6 membered heterocyclic ring contains at each occurrence 1 or 2 heteroatoms selected from N or O, and each 3-6 membered carbocyclic or 3-6 membered heterocyclic ring can optionally be by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyl, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR Substituents of 8 R 9 , -NR 8 C(=O)R 8 or -S(O) 2 NR 8 R 9 are substituted or unsubstituted; when
Figure 02_image024
selected from
Figure 02_image028
When each R 4a is absent, and one of R 4b and R 4c is absent, the other of R 4b and R 4c is selected from hydrogen, -F, -Cl, oxo, methyl, ethyl , propyl, isopropyl, -methylene-(halogen) 1-3 , -ethylene-(halogen) 1-3 , -propylene-(halogen) 1-3 , heteroethyl, heteropropyl group, -CN, -OR 8, - methylene - (OR 8) 1-3, - ethylidene - (OR 8) 1-3, - propylene - (OR 8) 1-3, -NR 8 R 9 , -methylene-NR 8 R 9 , -ethylene-NR 8 R 9 , -propylene-NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -methylene-C(=O)NR 8 R 9 , -ethylene-C(=O)NR 8 R 9 , -propylene-C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -methylene-NR 8 C(=O)R 8 , -ethylene-NR 8 C(=O)R 8 , -propylene-NR 8 C(=O)R 8 , -S(O) 2 NR 8 R 9 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl; each R 4b or R 4c is independently optionally replaced by 1, 2, 3, 4, 5, or 6 selected from -F, -Cl, methyl, ethyl, propyl, Isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(= Substituents of O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 Substituted or unsubstituted; R 8 and R 9 in each R 4a , R 4b or R 4c are independently selected at each occurrence from hydrogen, methyl, ethyl, propyl or isopropyl; or R 4a , R 8 and R 9 in R 4b or R 4c form together with the N atom to which they are commonly attached
Figure 02_image377
,
Figure 02_image379
or
Figure 02_image381
.

在一些實施方式中，當

Figure 02_image024
選自
Figure 02_image026
時，每個R4a 、R4b 和R4c 在每次出現時獨立地選自氫、-F、-Cl、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、
Figure 02_image377
、
Figure 02_image379
、
Figure 02_image381
、
Figure 02_image1037
、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、
Figure 02_image1039
、
Figure 02_image1041
、
Figure 02_image1043
、
Figure 02_image1045
、
Figure 02_image1047
、
Figure 02_image1049
、
Figure 02_image1051
、
Figure 02_image1053
、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、 -CH2 C(=O)N(CH3 )2 、-CH2 CH2 C(=O)N(CH3 )2 、-CH2 CH2 CH2 C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-CH2 NHC(=O)CH3 、-CH2 CH2 NHC(=O)CH3 、-CH2 CH2 CH2 NHC(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 N(CH3 )2 、3元碳環基、4元碳環基、5元碳環基或6元碳環基；每個R4a 、R4b 或R4c 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OH、-NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 ) -C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 的取代基取代或不取代；或R4b 和R4c 與它們共同連接的碳原子形成選自3元碳環、4元碳環、5元碳環、6元碳環、3元雜環、4元雜環、5元雜環或6元雜環的環，每個3-6元雜環在每次出現時包含1或2個選自N或O的雜原子，且每個3-6元碳環或3-6元雜環可選地可以被1、2、3、4、5或6個選自-F、-Cl、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OH、-NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 ) -C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 的取代基取代或不取代；或 當
Figure 02_image024
選自
Figure 02_image028
時，每個R4a 是不存在，且R4b 和R4c 中之一是不存在，R4b 和R4c 中的另一個選自氫、-F、-Cl、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、
Figure 02_image377
、
Figure 02_image379
、
Figure 02_image381
、
Figure 02_image1037
、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、
Figure 02_image1039
、
Figure 02_image1041
、
Figure 02_image1043
、
Figure 02_image1045
、
Figure 02_image1047
、
Figure 02_image1049
、
Figure 02_image1051
、
Figure 02_image1053
、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-CH2 C(=O)N(CH3 )2 、-CH2 CH2 C(=O)N(CH3 )2 、-CH2 CH2 CH2 C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-CH2 NHC(=O)CH3 、-CH2 CH2 NHC(=O)CH3 、-CH2 CH2 CH2 NHC(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 N(CH3 )2 、3元碳環基、4元碳環基、5元碳環基或6元碳環基；每個R4b 或R4c 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OH、-NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 ) -C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 的取代基取代或不取代。In some embodiments, when
Figure 02_image024
selected from
Figure 02_image026
, each R 4a , R 4b and R 4c at each occurrence is independently selected from hydrogen, -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2, -CF 3, -CH 2 CH 2 F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2, -NHCH 3, -NHCH 2 CH 3, -NHCH 2 CH 2 CH 3 , -NHCH (CH 3) 2, -N (CH 3) 2, -N (CH 3) CH 2 CH 3, -N (CH 3) CH 2 CH 2 CH 3, -N (CH 3) CH (CH 3 ) 2 ,
Figure 02_image377
,
Figure 02_image379
,
Figure 02_image381
,
Figure 02_image1037
, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 ,
Figure 02_image1039
,
Figure 02_image1041
,
Figure 02_image1043
,
Figure 02_image1045
,
Figure 02_image1047
,
Figure 02_image1049
,
Figure 02_image1051
,
Figure 02_image1053
, -C(=O)CH 3 , -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 CH 2 C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3) C (= O) CH 3, -CH 2 NHC (= O) CH 3, -CH 2 CH 2 NHC (= O) CH 3, -CH 2 CH 2 CH 2 NHC (= O) CH 3, - S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N(CH 3 ) 2 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl; each R 4a , R 4b or R 4c is independently optionally surrounded by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, methyl, ethyl, propyl radical, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CN, -C (=O)CH 3 , -C(=O)OCH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ) -C(=O )N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ) or the substituent of -S(O) 2 N(CH 3 ) 2 is substituted or unsubstituted; or R 4b and R 4c and the carbon atoms to which they are connected together form a carbon atom selected from the group consisting of 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle Carbocycle, 6-membered carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, or 6-membered heterocycle, each 3- to 6-membered heterocycle containing at each occurrence 1 or 2 selected from A heteroatom of N or O, and each 3-6 membered carbocycle or 3-6 membered heterocycle may optionally be replaced by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, methyl , ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CN, -C(=O)CH 3 , -C(=O)OCH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ) -C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 ) Substituents of C(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ) or -S(O) 2 N(CH 3 ) 2 substituted or unsubstituted ; or when
Figure 02_image024
selected from
Figure 02_image028
When each R 4a is absent, and one of R 4b and R 4c is absent, the other of R 4b and R 4c is selected from hydrogen, -F, -Cl, oxo, methyl, ethyl , propyl, isopropyl, -CH 2 F, -CHF 2, -CF 3, -CH 2 CH 2 F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 OCH 3, -CH 2 CH 2 OCH 3, -CH 2 CH 2 CH 2 OCH 3, -CN, -OH, -OCH 3, - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 3 , -N(CH 3 )CH 2 CH 2 CH 3 , -N(CH 3 )CH(CH 3 ) 2 ,
Figure 02_image377
,
Figure 02_image379
,
Figure 02_image381
,
Figure 02_image1037
, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 ,
Figure 02_image1039
,
Figure 02_image1041
,
Figure 02_image1043
,
Figure 02_image1045
,
Figure 02_image1047
,
Figure 02_image1049
,
Figure 02_image1051
,
Figure 02_image1053
, -C(=O)CH 3 , -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 CH 2 C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3) C (= O) CH 3, -CH 2 NHC (= O) CH 3, -CH 2 CH 2 NHC (= O) CH 3, -CH 2 CH 2 CH 2 NHC (= O) CH 3, - S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N(CH 3 ) 2 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl; each R 4b or R 4c independently optionally by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, methyl, ethyl, propyl, iso propyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CN, -C(=O )CH 3 , -C(=O)OCH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ) -C(=O)N( CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ) or - The substituent of S(O) 2 N(CH 3 ) 2 is substituted or unsubstituted.

在一些實施方式中，當

Figure 02_image024
選自
Figure 02_image026
時，每個R4a 、R4b 和R4c 在每次出現時獨立地選自氫、-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、
Figure 02_image377
、
Figure 02_image379
、
Figure 02_image381
、
Figure 02_image1037
、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、
Figure 02_image1039
、
Figure 02_image1041
、
Figure 02_image1043
、
Figure 02_image1045
、
Figure 02_image1047
、
Figure 02_image1049
、
Figure 02_image1051
、
Figure 02_image1053
、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-CH2 C(=O)N(CH3 )2 、-CH2 CH2 C(=O)N(CH3 )2 、-CH2 CH2 CH2 C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-CH2 NHC(=O)CH3 、-CH2 CH2 NHC(=O)CH3 、-CH2 CH2 CH2 NHC(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 N(CH3 )2 、3元碳環基、4元碳環基、5元碳環基或6元碳環基，或R4b 和R4c 與它們共同連接的碳原子形成選自3元碳環、4元碳環、5元碳環、6元碳環、3元雜環、4元雜環、5元雜環或6元雜環的環，每個3-6元雜環在每次出現時包含1或2個選自N或O的雜原子； 當
Figure 02_image024
選自
Figure 02_image028
時，每個R4a 是不存在，且R4b 和R4c 中之一是不存在，R4b 和R4c 中另一個選自氫、-F、-Cl、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、
Figure 02_image377
、
Figure 02_image379
、
Figure 02_image381
、
Figure 02_image1037
、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、
Figure 02_image1039
、
Figure 02_image1041
、
Figure 02_image1043
、
Figure 02_image1045
、
Figure 02_image1047
、
Figure 02_image1049
、
Figure 02_image1051
、
Figure 02_image1053
、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、-CH2 C(=O)N(CH3 )2 、-CH2 CH2 C(=O)N(CH3 )2 、-CH2 CH2 CH2 C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-CH2 NHC(=O)CH3 、-CH2 CH2 NHC(=O)CH3 、-CH2 CH2 CH2 NHC(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )、-S(O)2 N(CH3 )2 、3元碳環基、4元碳環基、5元碳環基或6元碳環基。In some embodiments, when
Figure 02_image024
selected from
Figure 02_image026
, each R 4a , R 4b and R 4c at each occurrence is independently selected from hydrogen, -F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2, -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 OCH 3, -CH 2 CH 2 OCH 3, -CH 2 CH 2 CH 2 OCH 3, -CN, -OH, -OCH 3, -OCH 2 CH 3, -OCH 2 CH 2 CH 3, -OCH (CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2, -NHCH 3, -NHCH 2 CH 3, -NHCH 2 CH 2 CH 3, -NHCH (CH 3 ) 2, -N (CH 3) 2, -N (CH 3) CH 2 CH 3, -N (CH 3) CH 2 CH 2 CH 3, -N (CH 3) CH(CH 3 ) 2 ,
Figure 02_image377
,
Figure 02_image379
,
Figure 02_image381
,
Figure 02_image1037
, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 ,
Figure 02_image1039
,
Figure 02_image1041
,
Figure 02_image1043
,
Figure 02_image1045
,
Figure 02_image1047
,
Figure 02_image1049
,
Figure 02_image1051
,
Figure 02_image1053
, -C(=O)CH 3 , -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 CH 2 C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3) C (= O) CH 3, -CH 2 NHC (= O) CH 3, -CH 2 CH 2 NHC (= O) CH 3, -CH 2 CH 2 CH 2 NHC (= O) CH 3, - S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N(CH 3 ) 2 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl Or 6-membered carbocyclyl, or R 4b and R 4c and the carbon atoms to which they are commonly attached form a carbon atom selected from the group consisting of 3-membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, 6-membered carbocycle, 3-membered heterocycle, 4-membered carbocycle A heterocycle, a 5-membered heterocycle or a 6-membered heterocycle, each 3-6 membered heterocycle containing in each occurrence 1 or 2 heteroatoms selected from N or O; when
Figure 02_image024
selected from
Figure 02_image028
When each R 4a is absent, and one of R 4b and R 4c is absent, the other of R 4b and R 4c is selected from hydrogen, -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2, -CF 3, -CH 2 CH 2 F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 OCH 3, -CH 2 CH 2 OCH 3, -CH 2 CH 2 CH 2 OCH 3, -CN, -OH, -OCH 3, -OCH 2 CH 3, -OCH 2 CH 2 CH 3, -OCH (CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2, -NHCH 3, - NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 3 , -N(CH 3 )CH 2 CH 2 CH 3 , -N(CH 3 )CH(CH 3 ) 2 ,
Figure 02_image377
,
Figure 02_image379
,
Figure 02_image381
,
Figure 02_image1037
, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 ,
Figure 02_image1039
,
Figure 02_image1041
,
Figure 02_image1043
,
Figure 02_image1045
,
Figure 02_image1047
,
Figure 02_image1049
,
Figure 02_image1051
,
Figure 02_image1053
, -C(=O)CH 3 , -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 CH 2 C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3) C (= O) CH 3, -CH 2 NHC (= O) CH 3, -CH 2 CH 2 NHC (= O) CH 3, -CH 2 CH 2 CH 2 NHC (= O) CH 3, - S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N(CH 3 ) 2 , 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl.

在一些實施方式中，當

Figure 02_image024
選自
Figure 02_image026
時，每個R4a 、R4b 和R4c 在每次出現時獨立地選自氫、-F、甲基、
Figure 02_image379
、-CH2 N(CH3 )2 、
Figure 02_image1043
、
Figure 02_image1047
、
Figure 02_image1049
； 當
Figure 02_image024
選自
Figure 02_image028
時，每個R4a 是不存在，且R4b 和R4c 中之一是不存在，R4b 和R4c 中另一個選自氫或甲基。In some embodiments, when
Figure 02_image024
selected from
Figure 02_image026
, each R 4a , R 4b and R 4c at each occurrence is independently selected from hydrogen, -F, methyl,
Figure 02_image379
, -CH 2 N(CH 3 ) 2 ,
Figure 02_image1043
,
Figure 02_image1047
,
Figure 02_image1049
; when
Figure 02_image024
selected from
Figure 02_image028
When each R 4a is absent, and one of R 4b and R 4c is absent, the other of R 4b and R 4c is selected from hydrogen or methyl.

在一些實施方式中，當

Figure 02_image024
選自
Figure 02_image026
，每個R4a 、R4b 和R4c 在每次出現時獨立地選自氫、-F、-CH2 F、甲基、
Figure 02_image379
、-CH2 N(CH3 )2 、
Figure 02_image1043
、
Figure 02_image1047
、
Figure 02_image1049
； 當
Figure 02_image024
選自
Figure 02_image028
時，每個R4a 是不存在，且R4b 和R4c 中之一是不存在，R4b 和R4c 中另一個選自氫或甲基。In some embodiments, when
Figure 02_image024
selected from
Figure 02_image026
, each R 4a , R 4b and R 4c at each occurrence is independently selected from hydrogen, -F, -CH 2 F, methyl,
Figure 02_image379
, -CH 2 N(CH 3 ) 2 ,
Figure 02_image1043
,
Figure 02_image1047
,
Figure 02_image1049
; when
Figure 02_image024
selected from
Figure 02_image028
When each R 4a is absent, and one of R 4b and R 4c is absent, the other of R 4b and R 4c is selected from hydrogen or methyl.

在一些實施方式中，R41 選自

Figure 02_image1092
或
Figure 02_image1094
。In some embodiments, R 41 is selected from
Figure 02_image1092
or
Figure 02_image1094
.

在一些實施方式中，R41 選自

Figure 02_image1092
。In some embodiments, R 41 is selected from
Figure 02_image1092
.

在一些實施方式中，每個R42 選自-F、-Cl、-Br、氧代、-C1-3 烷基、-C1-3 亞烷基-(鹵素)1-3 、雜C1-3 烷基、-C2-3 烯基、-C2-3 炔基、-OR8 、-C1-3 亞烷基-(OR8 )1-3 、-NR8 R9 、-C1-3 亞烷基-NR8 R9 、-CN、-C1-3 亞烷基-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-C1-3 亞烷基-C(=O)NR8 R9 、-NR8 C(=O)R8 、-C1-3 亞烷基-NR8 C(=O)R8 或-S(O)2 NR8 R9 ；每個R42 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、-Br、-C1-3 烷基、-C1-3 烷氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 、或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R42 中R8 和R9 在每次出現時獨立地選自氫或-C1-3 烷基。In some embodiments, each R 42 is selected from -F, -Cl, -Br, oxo, -C 1-3 alkyl, -C 1-3 alkylene-(halogen) 1-3 , heteroC 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -OR 8 , -C 1-3 alkylene -(OR 8 ) 1-3 , -NR 8 R 9 , - C 1-3 alkylene-NR 8 R 9 , -CN, -C 1-3 alkylene-CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O )R 8 , -C(=O)NR 8 R 9 , -C 1-3 alkylene -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -C 1-3 alkylene group -NR 8 C (= O) R 8 , or -S (O) 2 NR 8 R 9; each R 42 is independently optionally substituted 5 or 6 is selected from - F, -Cl, -Br, -C 1-3 alkyl, -C 1-3 alkoxy, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R The substituents of 9 are substituted or unsubstituted; R 8 and R 9 in each R 42 are independently selected at each occurrence from hydrogen or -C 1-3 alkyl.

在一些實施方式中，每個R42 選自-F、-Cl、氧代、甲基、乙基、丙基、異丙基、-亞甲基-(鹵素)1-3 、-亞乙基-(鹵素)1-3 、-亞丙基-(鹵素)1-3 、雜乙基、雜丙基、乙烯基、丙烯基、乙炔基、丙炔基、-OR8 、-亞甲基-(OR8 )1-3 、-亞乙基-(OR8 )1-3 、-亞丙基-(OR8 )1-3 、-NR8 R9 、-亞甲基-NR8 R9 、-亞乙基-NR8 R9 、-亞丙基-NR8 R9 、-CN、-亞甲基-CN、-亞乙基-CN、-丙基-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-亞甲基-C(=O)NR8 R9 、-亞乙基-C(=O)NR8 R9 、-亞丙基-C(=O)NR8 R9 、-NR8 C(=O)R8 、-亞甲基-NR8 C(=O)R8 、-亞乙基-NR8 C(=O)R8 、-亞丙基-NR8 C(=O)R8 或-S(O)2 NR8 R9 ；每個R42 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OR8 、-NR8 R9 、-CN、-C(=O)R8 、-C(=O)OR8 、-OC(=O)R8 、-C(=O)NR8 R9 、-NR8 C(=O)R8 ,或-S(O)2 NR8 R9 的取代基取代或不取代； 每個R42 中的R8 和R9 在每次出現時獨立地選自氫、甲基、乙基、丙基或異丙基。In some embodiments, each R 42 is selected from -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -methylene-(halogen) 1-3 , -ethylene -(halogen) 1-3 , -propylene-(halogen) 1-3 , heteroethyl, heteropropyl, vinyl, propenyl, ethynyl, propynyl, -OR 8 , -methylene- (OR 8 ) 1-3 , -ethylene-(OR 8 ) 1-3 , -propylene-(OR 8 ) 1-3 , -NR 8 R 9 , -methylene-NR 8 R 9 , -Ethylene-NR 8 R 9 , -Propylene-NR 8 R 9 , -CN, -methylene-CN, -Ethylene-CN, -propyl-CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(=O)NR 8 R 9 , -methylene-C(=O)NR 8 R 9 , -ethylene -C(=O)NR 8 R 9 , -propylene-C(=O)NR 8 R 9 , -NR 8 C(=O)R 8 , -methylene-NR 8 C(=O)R 8 , -ethylene-NR 8 C(=O)R 8 , -propylene-NR 8 C(=O)R 8 or -S(O) 2 NR 8 R 9 ; each R 42 can be independently optionally by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyl Oxygen, oxo, -OR 8 , -NR 8 R 9 , -CN, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -C(= O) NR 8 R 9 , -NR 8 C(=O)R 8 , or -S(O) 2 NR 8 R 9 is substituted or unsubstituted with substituents; R 8 and R 9 in each R 42 are in each The first occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

在一些實施方式中，每個R42 選自-F、-Cl、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、乙烯基、丙烯基、乙炔基、丙炔基、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-CN、-CH2 CN、-CH2 CH2 CN、-CH2 CH2 CN、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、 -CH2 C(=O)N(CH3 )2 、-CH2 CH2 C(=O)N(CH3 )2 、-CH2 CH2 CH2 C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-CH2 NHC(=O)CH3 、-CH2 CH2 NHC(=O)CH3 、-CH2 CH2 CH2 NHC(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 ；每個R42 獨立地可選地被1、2、3、4、5或6個選自-F、-Cl、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、氧代、-OH、-NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(=O)CH3 、-C(=O)OCH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 ) -C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 的取代基取代或不取代。In some embodiments, each R 42 is selected from -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2, -CF 3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 OCH 3, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , vinyl, propenyl, ethynyl, propynyl, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH (CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2, -NHCH 3, -NHCH 2 CH 3, -NHCH 2 CH 2 CH 3, -NHCH (CH 3) 2, -N (CH 3) 2, -N (CH 3) CH 2 CH 3, -N (CH 3) CH 2 CH 2 CH 3, -N (CH 3) CH (CH 3 ) 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , - CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CN, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CN, -C(=O)CH 3 , -C(=O) OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O) )NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 CH 2 C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -CH 2 NHC(= O)CH 3 , -CH 2 CH 2 NHC(=O)CH 3 , -CH 2 CH 2 CH 2 NHC(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH( CH 3), or -S (O) 2 N (CH 3) 2; each R42 is independently optionally selected by 1, 2, 3, 4, 5 or 6 selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl Oxy, isopropoxy, oxo, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CN, -C(=O)CH 3 , -C(=O)OCH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH(CH 3 ) -C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3, -N (CH 3) C (= O) CH 3, -S (O) 2 NH 2, -S (O) 2 NH (CH 3) or -S (O) 2 N (CH 3) 2 of Substituents are substituted or unsubstituted.

在一些實施方式中，每個R42 選自-F、-Cl、氧代、甲基、乙基、丙基、異丙基、-CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、乙烯基、丙烯基、乙炔基、丙炔基、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-CN、-CH2 CN、-CH2 CH2 CN、-CH2 CH2 CN、-C(=O)CH3 、-C(=O)OCH3 、-C(=O)OCH2 CH3 、-C(=O)OCH2 CH2 CH3 、-OC(=O)CH3 、-C(=O)NH2 、-C(=O)NH(CH3 )、-C(=O)N(CH3 )2 、 -CH2 C(=O)N(CH3 )2 、-CH2 CH2 C(=O)N(CH3 )2 、-CH2 CH2 CH2 C(=O)N(CH3 )2 、-NHC(=O)CH3 、-N(CH3 )C(=O)CH3 、-CH2 NHC(=O)CH3 、-CH2 CH2 NHC(=O)CH3 、-CH2 CH2 CH2 NHC(=O)CH3 、-S(O)2 NH2 、-S(O)2 NH(CH3 )或-S(O)2 N(CH3 )2 。In some embodiments, each R 42 is selected from -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2, -CF 3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 OCH 3, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , vinyl, propenyl, ethynyl, propynyl, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH (CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2, -NHCH 3, -NHCH 2 CH 3, -NHCH 2 CH 2 CH 3, -NHCH (CH 3) 2, -N (CH 3) 2, -N (CH 3) CH 2 CH 3, -N (CH 3) CH 2 CH 2 CH 3, -N (CH 3) CH (CH 3 ) 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , - CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CN, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CN, -C(=O)CH 3 , -C(=O) OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH 2 CH 2 CH 3 , -OC(=O)CH 3 , -C(=O)NH 2 , -C(=O) )NH(CH 3 ), -C(=O)N(CH 3 ) 2 , -CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 C(=O)N(CH 3 ) 2 , -CH 2 CH 2 CH 2 C(=O)N(CH 3 ) 2 , -NHC(=O)CH 3 , -N(CH 3 )C(=O)CH 3 , -CH 2 NHC(= O)CH 3 , -CH 2 CH 2 NHC(=O)CH 3 , -CH 2 CH 2 CH 2 NHC(=O)CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH( CH 3 ) or -S(O) 2 N(CH 3 ) 2 .

在一些實施方式中，每個R42 選自甲基、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、丙炔基、-CH2 OH、-CH2 CH2 OH、-CN、-CH2 CN或-C(=O)N(CH3 )2 。In some embodiments, each R 42 is selected from methyl, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , propyne group, -CH 2 OH, -CH 2 CH 2 OH, -CN, -CH 2 CN or -C(=O)N(CH 3 ) 2 .

在一些實施方式中，每個R4 獨立地選自：

Figure 02_image1097
、
Figure 02_image1099
、
Figure 02_image1101
、
Figure 02_image1103
、
Figure 02_image1105
、
Figure 02_image1107
、
Figure 02_image1109
、
Figure 02_image1111
、
Figure 02_image1113
、
Figure 02_image1115
、
Figure 02_image1117
、
Figure 02_image1119
、
Figure 02_image1121
、
Figure 02_image1123
、
Figure 02_image1125
、
Figure 02_image1127
、
Figure 02_image1129
、
Figure 02_image1131
、
Figure 02_image1133
、
Figure 02_image1135
、
Figure 02_image1137
、
Figure 02_image1139
、
Figure 02_image1141
、
Figure 02_image1143
、
Figure 02_image1145
、
Figure 02_image1147
、
Figure 02_image1149
、
Figure 02_image1151
、
Figure 02_image1153
、
Figure 02_image1155
、
Figure 02_image1157
、
Figure 02_image1159
、
Figure 02_image1161
、
Figure 02_image1163
、
Figure 02_image1165
、
Figure 02_image1167
、
Figure 02_image1169
、
Figure 02_image1171
、
Figure 02_image1173
、
Figure 02_image1175
、
Figure 02_image1177
、
Figure 02_image1179
、
Figure 02_image1181
、
Figure 02_image1183
、
Figure 02_image1185
、
Figure 02_image1187
、
Figure 02_image1189
、 或
Figure 02_image1191
。 In some embodiments, each R 4 is independently selected from:
Figure 02_image1097
,
Figure 02_image1099
,
Figure 02_image1101
,
Figure 02_image1103
,
Figure 02_image1105
,
Figure 02_image1107
,
Figure 02_image1109
,
Figure 02_image1111
,
Figure 02_image1113
,
Figure 02_image1115
,
Figure 02_image1117
,
Figure 02_image1119
,
Figure 02_image1121
,
Figure 02_image1123
,
Figure 02_image1125
,
Figure 02_image1127
,
Figure 02_image1129
,
Figure 02_image1131
,
Figure 02_image1133
,
Figure 02_image1135
,
Figure 02_image1137
,
Figure 02_image1139
,
Figure 02_image1141
,
Figure 02_image1143
,
Figure 02_image1145
,
Figure 02_image1147
,
Figure 02_image1149
,
Figure 02_image1151
,
Figure 02_image1153
,
Figure 02_image1155
,
Figure 02_image1157
,
Figure 02_image1159
,
Figure 02_image1161
,
Figure 02_image1163
,
Figure 02_image1165
,
Figure 02_image1167
,
Figure 02_image1169
,
Figure 02_image1171
,
Figure 02_image1173
,
Figure 02_image1175
,
Figure 02_image1177
,
Figure 02_image1179
,
Figure 02_image1181
,
Figure 02_image1183
,
Figure 02_image1185
,
Figure 02_image1187
,
Figure 02_image1189
, or
Figure 02_image1191
.

在一些實施方式中，每個R4 獨立地選自：

Figure 02_image1097
、
Figure 02_image1099
、
Figure 02_image1101
、
Figure 02_image1103
、
Figure 02_image1105
、
Figure 02_image1107
、
Figure 02_image1109
、
Figure 02_image1111
、
Figure 02_image1113
、
Figure 02_image1115
、
Figure 02_image1117
、
Figure 02_image1119
、
Figure 02_image1121
、
Figure 02_image1123
、
Figure 02_image1125
、
Figure 02_image1127
、
Figure 02_image1129
、
Figure 02_image1131
、
Figure 02_image1133
、
Figure 02_image1135
、
Figure 02_image1137
、
Figure 02_image1139
、
Figure 02_image1141
、
Figure 02_image1143
、
Figure 02_image1145
、
Figure 02_image1147
、
Figure 02_image1149
、
Figure 02_image1151
、
Figure 02_image1153
、
Figure 02_image1155
、
Figure 02_image1157
、
Figure 02_image1159
、
Figure 02_image1161
、
Figure 02_image1163
、
Figure 02_image1165
、
Figure 02_image1167
、
Figure 02_image1169
、
Figure 02_image1171
、
Figure 02_image1173
、
Figure 02_image1175
、
Figure 02_image1177
、
Figure 02_image1179
、
Figure 02_image1181
、
Figure 02_image1183
、
Figure 02_image1185
、
Figure 02_image1187
、
Figure 02_image1189
、
Figure 02_image1191
、
Figure 02_image1241
、
Figure 02_image1243
、
Figure 02_image1245
或
Figure 02_image1247
。       In some embodiments, each R 4 is independently selected from:
Figure 02_image1097
,
Figure 02_image1099
,
Figure 02_image1101
,
Figure 02_image1103
,
Figure 02_image1105
,
Figure 02_image1107
,
Figure 02_image1109
,
Figure 02_image1111
,
Figure 02_image1113
,
Figure 02_image1115
,
Figure 02_image1117
,
Figure 02_image1119
,
Figure 02_image1121
,
Figure 02_image1123
,
Figure 02_image1125
,
Figure 02_image1127
,
Figure 02_image1129
,
Figure 02_image1131
,
Figure 02_image1133
,
Figure 02_image1135
,
Figure 02_image1137
,
Figure 02_image1139
,
Figure 02_image1141
,
Figure 02_image1143
,
Figure 02_image1145
,
Figure 02_image1147
,
Figure 02_image1149
,
Figure 02_image1151
,
Figure 02_image1153
,
Figure 02_image1155
,
Figure 02_image1157
,
Figure 02_image1159
,
Figure 02_image1161
,
Figure 02_image1163
,
Figure 02_image1165
,
Figure 02_image1167
,
Figure 02_image1169
,
Figure 02_image1171
,
Figure 02_image1173
,
Figure 02_image1175
,
Figure 02_image1177
,
Figure 02_image1179
,
Figure 02_image1181
,
Figure 02_image1183
,
Figure 02_image1185
,
Figure 02_image1187
,
Figure 02_image1189
,
Figure 02_image1191
,
Figure 02_image1241
,
Figure 02_image1243
,
Figure 02_image1245
or
Figure 02_image1247
.

在一些實施方式中，所述的選自： 1.          2-(1-丙烯醯基-4-(2-(((1r,4r)-4-(二甲基氨基)環己基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 2.          2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(2-甲基-1-氧代-1,2-二氫異喹啉-8-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 3.          2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 4.          2-(1-丙烯醯基-4-(7-(萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 5.          2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環己基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 6.          2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環己基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 7.          2-(1-丙烯醯基-4-(2-(3-(二甲基氨基)環丁氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 8.          2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環丁基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 9.          2-(1-丙烯醯基-4-(2-((1-(二甲基氨基)環丁基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 10.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環己基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 11.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環己基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 12.     2-(1-丙烯醯基-4-(2-((1-(二甲基氨基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 13.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 14.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 15.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環己基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 16.     2-(1-丙烯醯基-4-(2-((2-(4-甲基哌啶-1-基)環戊基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 17.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 18.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環己基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 19.     2-(1-丙烯醯基-4-(2-((2-((二甲基氨基)甲基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 20.     2-(1-丙烯醯基-4-(2-((1-(二甲基氨基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 21.     2-(1-丙烯醯基-4-(2-(2-(2-(二甲基氨基)環戊基)乙氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 22.     2-(1-丙烯醯基-4-(2-(((1R,3S)-3-(二甲基氨基)環戊基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 23.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 24.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 25.     2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((2-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 26.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(3-氟-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 27.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 28.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(2,3-二甲基氨基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 29.     2-(1-丙烯醯基-4-(7-(2-氯-3-氟苯基)-2-((3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 30.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)甲氧基)-7-(4-(三氟甲基)吡啶-3-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 31.     2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 32.     2-(1-丙烯醯基-4-(7-(萘-1-基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 33.     2-(1-丙烯醯基-4-(7-(萘-1-基)-2-((3-(吡咯烷-1-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 34.     2-(1-丙烯醯基-4-(7-(3-氟-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 35.     2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 36.     2-(1-丙烯醯基-4-(2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-7-(2-(三氟甲基)吡啶-3-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 37.     2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 38.     2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 39.     2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(3-氯-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 40.     2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(嗎福林甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 41.     2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 42.     2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 43.     2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 44.     2-(1-丙烯醯基-4-(7-(萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 45.     2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 46.     2-(1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 47.     2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 48.     2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(2,3-二甲基氨基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 49.     2-(1-丙烯醯基-4-(2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 50.     2-(1-丙烯醯基-4-(7-(苯并[b]噻吩-7-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 51.     2-(1-丙烯醯基-4-(7-(苯并[b]噻吩-4-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 52.     2-(1-丙烯醯基-4-(7-(苯并[d]噻唑-4-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 53.     2-(1-丙烯醯基-4-(7-(2,3-苯并呋喃-7-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 54.     2-(1-丙烯醯基-4-(7-(苯并[d]噻唑-7-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 55.     2-(1-丙烯醯基-4-(7-(2-氨基-6-氟苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 56.     2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 57.     2-(1-丙烯醯基-4-(2-(1-(1-((二甲基氨基)甲基)環丙基)乙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 58.     2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-((4-甲基哌嗪-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 59.     2-(1-丙烯醯基-4-(2-((1-((3-(二甲基氨基)氮雜環丁烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 60.     2-(1-丙烯醯基-4-(2-(((1S,2S)-2-(二甲基氨基)環己基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 61.     2-(1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 62.     2-(1-丙烯醯基-4-(2-((1-((3-氟氮雜環丁烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 63.     2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-(4-甲基哌嗪-1-羰基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 64.     2-(1-丙烯醯基-4-(2-((1-(((2-(二甲基氨基)乙基)(甲基)氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 65.     2-(1-丙烯醯基-4-(2-((1-(((S)-3-(二甲基氨基)吡咯烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 66.     2-(4-(2-((1-((4-乙醯基哌嗪-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-丙烯醯基哌嗪-2-基)乙腈； 67.     (S)-2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 68.     (S,E)-2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(4-氟丁-2-烯醯基)哌嗪-2-基)乙腈； 69.     (E)-2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(4-羥基丁-2-烯醯基)哌嗪-2-基)乙腈； 70.     (E)-2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(4-甲氧基丁-2-烯醯基)哌嗪-2-基)乙腈； 71.     2-(1-(2-氟丙烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-((4-甲基哌嗪-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 72.     2-(1-(2-氟丙烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 73.     2-(4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 74.     (E)-2-(1-(丁-2-烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 75.     2-(4-(2-((1-((3-(二甲基氨基)氮雜環丁烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 76.     2-(4-(2-((1-((二乙基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 77.     (E)-2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(4-氟丁-2-烯醯基)哌嗪-2-基)乙腈； 78.     2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 79.     2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 80.     2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(2,3-二甲基氨基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 81.     2-(4-(2-((1-((3,3-二氟吡咯烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 82.     (E)-2-(1-(丁-2-烯醯基)-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(2,3-二甲基氨基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 83.     (S)-2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 84.     (S,E)-2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(4-氟丁-2-烯醯基)哌嗪-2-基)乙腈； 85.     (E)-2-(1-(4-(二甲基氨基)丁-2-烯醯基)-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈；或 86.     (E)-2-(1-(4-(二甲基氨基)丁-2-烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈。 In some embodiments, described is selected from: 1. 2-(1-Propenyl-4-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)oxy)-7-(naphthalen-1-yl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 2. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(2-methyl-1-oxo- 1,2-Dihydroisoquinolin-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 3. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(5-methyl-1H-indazole- 4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 4. 2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 5. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclohexyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 6. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclohexyl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 7. 2-(1-Propenyl-4-(2-(3-(dimethylamino)cyclobutoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyridine iso[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 8. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclobutyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 - Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 9. 2-(1-Propenyl-4-(2-((1-(dimethylamino)cyclobutyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 - Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 10. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclohexyl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 11. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclohexyl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 12. 2-(1-Propenyl-4-(2-((1-(dimethylamino)cyclopropyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 - Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 13. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)oxy)-7-(naphthalen-1-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 14. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 - Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 15. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclohexyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 16. 2-(1-Propenyl-4-(2-((2-(4-methylpiperidin-1-yl)cyclopentyl)oxy)-7-(naphthalen-1-yl)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 17. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 - Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 18. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclohexyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 19. 2-(1-Propenyl-4-(2-((2-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(naphthalen-1-yl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 20. 2-(1-Propenyl-4-(2-((1-(dimethylamino)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; twenty one. 2-(1-Propenyl-4-(2-(2-(2-(dimethylamino)cyclopentyl)ethoxy)-7-(naphthalen-1-yl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; twenty two. 2-(1-Propenyl-4-(2-(((1R,3S)-3-(dimethylamino)cyclopentyl)methoxy)-7-(8-methylnaphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; twenty three. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; twenty four. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 25. 2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((2-(dimethylamino)cyclopentyl)methoxy)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 26. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(3-fluoro-2-(trifluoromethyl)phenyl) )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 27. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 28. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(2,3-dimethylamino)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 29. 2-(1-Propenyl-4-(7-(2-chloro-3-fluorophenyl)-2-((3-(dimethylamino)cyclopentyl)methoxy)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 30. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)methoxy)-7-(4-(trifluoromethyl)pyridin-3-yl) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 31. 2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((3-(dimethylamino)cyclopentyl)methoxy)-5,6,7,8 - Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 32. 2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 33. 2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-((3-(pyrrolidin-1-yl)cyclopentyl)methoxy)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 34. 2-(1-Propenyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 35. 2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 36. 2-(1-Propenyl-4-(2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-7-(2-(trifluoromethyl)pyridine- 3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 37. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(naphthalen-1-yl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 38. 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 39. 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(3-chloro-2-( trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 40. 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(mfolinmethyl)cyclopropyl)methoxy) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 41. 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(naphthalen-1-yl)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 42. 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-chloronaphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 43. 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-methylnaphthalene-1 -yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 44. 2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclobutyl)methoxy)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 45. 2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclobutyl)methoxy) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 46. 2-(1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 47. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 48. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(2,3-dimethylamino)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 49. 2-(1-Propenyl-4-(2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8 -methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 50. 2-(1-Propenyl-4-(7-(benzo[b]thiophen-7-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 51. 2-(1-Propenyl-4-(7-(benzo[b]thiophen-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 52. 2-(1-Propenyl-4-(7-(benzo[d]thiazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 53. 2-(1-Propenyl-4-(7-(2,3-benzofuran-7-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 54. 2-(1-Propenyl-4-(7-(benzo[d]thiazol-7-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 55. 2-(1-Propenyl-4-(7-(2-amino-6-fluorophenyl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 56. 2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 57. 2-(1-Propenyl-4-(2-(1-(1-((dimethylamino)methyl)cyclopropyl)ethoxy)-7-(8-methylnaphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 58. 2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-((4-methylpiperazin-1-yl)methyl)cyclopropane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 59. 2-(1-Propenyl-4-(2-((1-((3-(dimethylamino)azetidin-1-yl)methyl)cyclopropyl)methoxy)- 7-(8-Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 60. 2-(1-Propenyl-4-(2-(((1S,2S)-2-(dimethylamino)cyclohexyl)oxy)-7-(naphthalen-1-yl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 61. 2-(1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 62. 2-(1-Propenyl-4-(2-((1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 63. 2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(4-methylpiperazine-1-carbonyl)cyclopropyl)methoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 64. 2-(1-Propenyl-4-(2-((1-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)cyclopropyl)methoxy)- 7-(8-Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 65. 2-(1-Propenyl-4-(2-((1-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy) -7-(8-Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 66. 2-(4-(2-((1-((4-Acetylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-propenylpiperazin-2-yl)acetonitrile; 67. (S)-2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl) methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 68. (S,E)-2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-fluorobut-2-enyl)piperazin-2-yl)acetonitrile; 69. (E)-2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-hydroxybut-2-enyl)piperazin-2-yl)acetonitrile; 70. (E)-2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-methoxybut-2-enyl)piperazin-2-yl)acetonitrile; 71. 2-(1-(2-Fluoropropenyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-((4-methylpiperazin-1-yl) methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 72. 2-(1-(2-Fluoropropenyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 73. 2-(4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 74. (E)-2-(1-(But-2-enyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl) yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 75. 2-(4-(2-((1-((3-(dimethylamino)azetidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-methyl) naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoropropenyl)piperazin-2-yl ) acetonitrile; 76. 2-(4-(2-((1-((diethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 77. (E)-2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-fluorobut-2-enyl)piperazin-2-yl)acetonitrile; 78. 2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 79. 2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7, 8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 80. 2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(2,3-dimethylamino)-5,6,7, 8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 81. 2-(4-(2-((1-((3,3-Difluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 82. (E)-2-(1-(But-2-enyl)-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-( 2,3-Dimethylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 83. (S)-2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 84. (S,E)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-fluorobut-2-enyl)piperazin-2-yl)acetonitrile; 85. (E)-2-(1-(4-(Dimethylamino)but-2-enyl)-4-(2-((1-((dimethylamino)methyl)cyclopropyl) Methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl ) acetonitrile; or 86. (E)-2-(1-(4-(Dimethylamino)but-2-enyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1- (pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl ) acetonitrile.

在一些實施方式中，所述的化合物選自： 87.     (S)-2-(1-丙烯醯基-4-(7-(3-氟-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 88.     (S)-2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 89.     (S)-2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 90.     2-(1-丙烯醯基-4-(7-(5-氯-4-(三氟甲基)吡啶-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 91.     (S)-2-(1-丙烯醯基-4-(7-(5-氯-4-(三氟甲基)吡啶-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 92.     (S)-2-(1-(2-氟丙烯醯基)-4-(2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-7-(2-(三氟甲基)吡啶-3-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 93.     (S)-2-(1-(2-氟丙烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 94.     2-(4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 95.     (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 96.     2-(1-丙烯醯基-4-(2-((1-((3,3-二氟吡咯烷-1-基)甲基)環丙基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 97.     2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(((S)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 98.     (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 99.     (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 100.                  (S)-2-(1-丙烯醯基-4-(7-(3-甲基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 101.                  (S)-2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 102.                  2-((S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((1-((S)-3-氟吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 103.                  2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(2,3-二氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 104.                  (S)-2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(3-氯-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 105.                  (S)-2-(4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(3-氯-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 106.                  (S)-2-(4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 107.                  (S)-2-(4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 108.                  (S)-2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-(嗎福林甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 109.                  (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-(嗎福林甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 110.                  2-((S)-1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-(((1R,2S)-2-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 111.                  2-((S)-4-(7-(8-氯萘-1-基)-2-(((1S,2R)-2-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 112.                  2-((S)-1-((E)-丁-2-烯醯基)-4-(7-(8-氯萘-1-基)-2-(((1S,2S)-2-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 113.                  2-((S)-4-(7-(8-氯萘-1-基)-2-(((1R,2R)-2-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-((E)-4-氟丁-2-烯醯基)哌嗪-2-基)乙腈； 114.                  2-((S)-4-(7-(8-氯萘-1-基)-2-(((1R,3S)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 115.                  2-((S)-1-((E)-丁-2-烯醯基)-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(((1S,3R)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 116.                  2-((S)-1-丙烯醯基-4-(2-(((1R,3R)-3-(二甲基氨基)環戊基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 117.                  2-((S)-4-(7-(2,3-二氯苯基)-2-(((1S,3S)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-((E)-4-氟丁-2-烯醯基)哌嗪-2-基)乙腈； 118.                  2-((S)-1-丙烯醯基-4-(2-(((1R,3S)-3-(二甲基氨基)環戊基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 119.                  2-((S)-1-丙烯醯基-4-(2-(((1R,3R)-3-(二甲基氨基)環戊基)甲氧基)-7-(4-(三氟甲基)吡啶-3-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 120.                  2-((S)-4-(7-(5-氯-4-(三氟甲基)吡啶-3-基)-2-(((1S,3S)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 121.                  2-((S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(((1S,3R)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 122.                  2-((S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-(((1R,3R)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 123.                  2-((S)-1-丙烯醯基-4-(2-(((1R,3R)-3-(二甲基氨基)環戊基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 124.                  2-((S)-4-(7-(8-氯萘-1-基)-2-(((1S,3R)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 125.                  2-(4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((3-甲氧基吡咯烷-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 126.                  (E)-2-(1-(丁-2-烯醯基)-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((4-甲基哌嗪-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 127.                  2-(4-(2-((1-((6-氮雜螺[2.5]辛基-6-基)甲基)環丙基)甲氧基)-7-(3-氯-2-甲基苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-丙烯醯基哌嗪-2-基)乙腈； 128.                  2-(1-丙烯醯基-4-(2-((1-((4-甲氧基哌啶-1-基)甲基)環丙基)甲氧基)-7-(4-甲基-3,4-二氫-2H-苯并[b][1,4]惡嗪-5-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 129.                  2-(1-丙烯醯基-4-(2-((1-((4-甲氧基哌啶-1-基)甲基)環丙基)甲氧基)-7-(1-甲基吲哚-7-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 130.                  2-(4-(2-((1-(((1R,4R)-2-氧雜-5-氮雜雙環[2.2.1]庚烷-5-基)甲基)環丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-丙烯醯基哌嗪-2-基)乙腈； 131.                  2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(1-(2-(吡咯烷-1-基)乙基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 132.                  2-(1-丙烯醯基-4-(7-(3-甲基-2-(三氟甲基)苯基)-2-(2-(1-(吡咯烷-1-基)環丙基)乙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 133.                  2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(1-甲基哌啶-3-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 134.                  (E)-2-(1-(丁-2-烯醯基)-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((6-甲基-2,6-二氮雜螺[3.3]庚烷-2-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 135.                  2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((二乙基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 136.                  2-(1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 137.                  (S)-2-(1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 138.                  (S)-2-(1-丙烯醯基-4-(2-((1-(吡咯烷-1-基)環丙基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 139.                  (S)-2-(1-丙烯醯基-4-(2-((1-(3,3-二氟吡咯烷-1-基)環丙基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 140.                  2-((2S)-1-丙烯醯基-4-(7-(3-氟-2-(三氟甲基)苯基)-2-((1-(1-甲基吡咯烷-2-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 141.                  2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(4-羥基-1-甲基吡咯烷-2-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 142.                  2-((2S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((2-甲基-1-(1-甲基吡咯烷-2-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 143.                  2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-(1-(吡咯烷-1-基甲基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 144.                  2-(1-丙烯醯基-4-(2-(1-((二甲基氨基)甲基)環丙氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 145.                  2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-(1-(1-甲基吡咯烷-2-基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈 146.                  2-((2S)-4-(7-(8-氯萘-1-基)-2-(1-(4,4-二氟-1-甲基吡咯烷-2-基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 147.                  2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-(1-(4-羥基-1-甲基吡咯烷-2-基)-2,2-二甲基環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 148.                  2-((2S)-4-(7-(2-氯-3-氟苯基)-2-(1-(4-甲氧基-1-甲基吡咯烷-2-基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-((E)-4-(二甲基氨基)丁-2-烯醯基)哌嗪-2-基)乙腈； 149.                  2-((2S)-4-(2-(2-(二甲基氨基)環丙氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈； 150.                  2-((2S)-1-((E)-丁-2-烯醯基)-4-(2-(2-((二甲基氨基)甲基)環丙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 151.                  2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 152.                  2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-氟苯基)-2-((2-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 153.                  2-((2S)-1-丙烯醯基-4-(2-((1R)-1-(2-(吡咯烷-1-基甲基)環丙基)乙氧基)-7-(鄰甲苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 154.                  2-((2S)-1-丙烯醯基-4-(7-(3-氟-2-甲基苯基)-2-((1R)-1-(2-((1-甲基吡咯烷-2-基)甲基)環丙基)乙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 155.                  (S)-2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-(1-(吡咯烷-1-基甲基)環丁氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 156.                  2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(1-((1-甲基吡咯烷-2-基)甲基)環丁氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 157.                  2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(1-(1-甲基吡咯烷-2-基)環丁氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 158.                  2-((2S)-1-丙烯醯基-4-(2-(2-(二甲基氨基)環丁氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 159.                  (S)-2-(1-丙烯醯基-4-(2-(3-(乙基(甲基)氨基)環丁氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 160.                  (S)-2-(1-丙烯醯基-4-(2-(3-(乙基(2-甲氧基乙基)氨基)環丁氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 161.                  2-((2S)-1-丙烯醯基-4-(2-(3-(二甲基氨基)-2-(2-甲氧基乙基)環丁氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 162.                  (S)-2-(1-丙烯醯基-4-(7-(萘-1-基)-2-(3-(吡咯烷-1-基)環丁氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 163.                  (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(吡咯烷-1-基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 164.                  2-((2S)-1-丙烯醯基-4-(2-((1-(1-甲基吡咯烷-3-基)環丁基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 165.                  2-((2S)-1-丙烯醯基-4-(2-((1-(1-甲基吡咯烷-2-基)環丁基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 166.                  2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環丁基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 167.                  (S)-2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((3-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 168.                  2-((S)-1-丙烯醯基-4-(2-((R)-1-(3-(二甲基氨基)環丁基)乙氧基)-7-(3-氟-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 169.                  (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 170.                  2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)-3-(三氟甲基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 171.                  2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)-3-(三氟甲氧基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 172.                  3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)環戊烷-1-腈； 173.                  乙基 3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)環戊烷-1-羧酸酯； 174.                  3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)-N,N-二甲基環戊烷-1-甲醯胺； 175.                  2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)-3-(吡咯烷-1-羧基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 176.                  3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)-N-甲基環戊烷-1-甲醯胺； 177.                  2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)-3-(噻唑-2-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 178.                  (S)-2-(1-丙烯醯基-4-(7-(2,3-二氟苯基)-2-((1-(吡咯烷-1-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 179.                  2-((2S)-1-丙烯醯基-4-(2-((1-(1-甲基吡咯烷-2-基)環戊基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 180.                  2-((2S)-1-丙烯醯基-4-(7-(2-氯-3-氟苯基)-2-((2,2-二氟-1-(1-甲基吡咯烷-2-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 181.                  2-((2S)-1-丙烯醯基-4-(7-(2-氯-3-氟苯基)-2-((1-(1-甲基吡咯烷-3-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 182.                  2-((2S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((1-(1-異丙基吡咯烷-3-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 183.                  (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-((二甲基氨基)甲基)環戊基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 184.                  (S)-2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環戊基)氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 185.                  (S)-2-(1-丙烯醯基-4-(7-(3-氟-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環戊基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 186.                  2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((1-甲基吡咯烷-2-基)甲基)環戊基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 187.                  2-((2S)-1-丙烯醯基-4-(2-((1-((4,4-二氟-1-甲基吡咯烷-2-基)甲基)環戊基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 188.                  2-((2S)-1-丙烯醯基-4-(2-((1-(二氟(1-甲基吡咯烷-2-基)甲基)環戊基)氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 189.                  2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 190.                  2-((2S)-1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 191.                  2-((2S)-1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 192.                  2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 193.                  (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-((二甲基氨基)甲基)環己基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 194.                  (S)-2-(1-丙烯醯基-4-(2-((1-(吡咯烷-1-基甲基)環己基)氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 195.                  2-((2S)-1-丙烯醯基-4-(7-(2-氯-3-氟苯基)-2-((2-(二甲基氨基)環己基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 196.                  2-((2S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((2-(1-甲基氮雜環丁烷-2-基)環己基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 197.                  2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((2-(二甲基氨基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 198.                  2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環己基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 199.                  (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 200.                  (S)-2-(1-丙烯醯基-4-(7-(2,3-二氟苯基)-2-((1-((二甲基氨基)甲基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 201.                  (S)-2-(1-丙烯醯基-4-(2-((4-(二甲基氨基)環己基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 202.                  2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((2-(吡咯烷-1-基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 203.                  2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((3-(二甲基氨基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 204.                  2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((3-(二甲基氨基)環己基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈； 205.                  N-(3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)環戊基)乙醯胺； 206.                  3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)-N,N-二甲基環戊烷-1-磺醯胺； 207.                  2-((2S)-1-丙烯醯基-4-(2-(((2-(二甲基氨基)環丁基)甲基)硫基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈；或 208.                  2-((2S)-1-丙烯醯基-4-(2-(((2-(二甲基氨基)環丁基)甲基)氨基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈。 In some embodiments, the compound is selected from: 87. (S)-2-(1-Propenyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl) )cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 88. (S)-2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methan oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 89. (S)-2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl) )cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 90. 2-(1-Propenyl-4-(7-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2-((1-(pyrrolidin-1-ylmethyl) cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 91. (S)-2-(1-Propenyl-4-(7-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2-((1-(pyrrolidine-1- ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 92. (S)-2-(1-(2-Fluoropropenyl)-4-(2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-7-(2 -(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 93. (S)-2-(1-(2-Fluoropropenyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl) )cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 94. 2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7, 8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 95. (S)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 96. 2-(1-Propenyl-4-(2-((1-((3,3-difluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-7-(3- Methyl-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 97. 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(((S)-3-fluoropyrrolidine-1 -yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 98. (S)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 99. (S)-2-(4-(7-(8-Chloro-7-fluoronaphthalen-1-yl)-2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 100. (S)-2-(1-Propenyl-4-(7-(3-methyl-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-yl) cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 101. (S)-2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-yl)cycle) propyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 102. 2-((S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((1-((S)-3-fluoropyrrolidin-1-yl) cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 103. 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(2,3-dichlorobenzene yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 104. (S)-2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(3-chloro -2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 105. (S)-2-(4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(3-chloro-2-(trifluoro) Methyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoropropenyl)piperazin-2-yl) Acetonitrile; 106. (S)-2-(4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-chloronaphthalen-1-yl) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 107. (S)-2-(4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 108. (S)-2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(mfolinmethyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 109. (S)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-(Mofolinmethyl)cyclopropyl)methoxy)-5,6,7,8 - Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 110. 2-((S)-1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((1R,2S)-2-(dimethylamino)cyclobutyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 111. 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((1S,2R)-2-(dimethylamino)cyclobutyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 112. 2-((S)-1-((E)-But-2-enyl)-4-(7-(8-chloronaphthalen-1-yl)-2-(((1S,2S)-2 -(dimethylamino)cyclobutyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 113. 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((1R,2R)-2-(dimethylamino)cyclobutyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enyl)piperazin-2-yl ) acetonitrile; 114. 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((1R,3S)-3-(dimethylamino)cyclopentyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 115. 2-((S)-1-((E)-But-2-enyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((( 1S,3R)-3-(dimethylamino)cyclopentyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine- 2-yl) acetonitrile; 116. 2-((S)-1-Propenyl-4-(2-(((1R,3R)-3-(dimethylamino)cyclopentyl)methoxy)-7-(3-methyl) -2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 117. 2-((S)-4-(7-(2,3-Dichlorophenyl)-2-(((1S,3S)-3-(dimethylamino)cyclopentyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enyl)piperazin-2-yl ) acetonitrile; 118. 2-((S)-1-Propenyl-4-(2-(((1R,3S)-3-(dimethylamino)cyclopentyl)methoxy)-7-(3-methyl -2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 119. 2-((S)-1-Propenyl-4-(2-(((1R,3R)-3-(dimethylamino)cyclopentyl)methoxy)-7-(4-(tris) Fluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 120. 2-((S)-4-(7-(5-Chloro-4-(trifluoromethyl)pyridin-3-yl)-2-(((1S,3S)-3-(dimethylamino) Cyclopentyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoropropenyl)piperazine-2- base) acetonitrile; 121. 2-((S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,3R)-3-(dimethyl) (ylamino)cyclopentyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 122. 2-((S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-(((1R,3R)-3-(dimethylamino)cyclopentyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 123. 2-((S)-1-Propenyl-4-(2-(((1R,3R)-3-(dimethylamino)cyclopentyl)methoxy)-7-(8-methyl) Naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 124. 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((1S,3R)-3-(dimethylamino)cyclopentyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 125. 2-(4-(7-(3-Chloro-2-(trifluoromethyl)phenyl)-2-((1-((3-methoxypyrrolidin-1-yl)methyl)cyclopropane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoropropenyl)piperazin-2-yl) Acetonitrile; 126. (E)-2-(1-(But-2-enyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((4 -Methylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine- 2-yl) acetonitrile; 127. 2-(4-(2-((1-((6-Azaspiro[2.5]octyl-6-yl)methyl)cyclopropyl)methoxy)-7-(3-chloro-2- methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-acryloylpiperazin-2-yl)acetonitrile; 128. 2-(1-Propenyl-4-(2-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-7-(4-methyl) yl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine- 4-yl)piperazin-2-yl)acetonitrile; 129. 2-(1-Propenyl-4-(2-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-7-(1-methyl) ylindol-7-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 130. 2-(4-(2-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methane oxy)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-propenylpiperazine -2-yl)acetonitrile; 131. 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(1-(2-(pyrrolidin-1-yl)ethyl) cyclopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 132. 2-(1-Propenyl-4-(7-(3-methyl-2-(trifluoromethyl)phenyl)-2-(2-(1-(pyrrolidin-1-yl)cyclopropane) yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 133. 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(1-methylpiperidin-3-yl)cycle propyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 134. (E)-2-(1-(But-2-enyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((6 -Methyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 135. 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((diethylamino)methyl)cyclopropyl) )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 136. 2-(1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 137. (S)-2-(1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methan oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 138. (S)-2-(1-Propenyl-4-(2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)-7-(2-(trifluoromethyl) phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 139. (S)-2-(1-Propenyl-4-(2-((1-(3,3-difluoropyrrolidin-1-yl)cyclopropyl)methoxy)-7-(3- Methyl-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 140. 2-((2S)-1-Propenyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-((1-(1-methylpyrrolidine-2 -yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 141. 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(4-hydroxy-1-methyl) Pyrrolidin-2-yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 142. 2-((2S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((2-methyl-1-(1-methylpyrrolidine-2- yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 143. 2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropoxy)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 144. 2-(1-Propenyl-4-(2-(1-((dimethylamino)methyl)cyclopropoxy)-7-(naphthalen-1-yl)-5,6,7,8 - Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 145. 2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-(1-(1-methylpyrrolidin-2-yl)cyclopropoxy)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 146. 2-((2S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(1-(4,4-difluoro-1-methylpyrrolidin-2-yl)cyclopropoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 147. 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-(1-(4-hydroxy-1-methylpyrrolidin-2-yl)-2, 2-Dimethylcyclopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 148. 2-((2S)-4-(7-(2-Chloro-3-fluorophenyl)-2-(1-(4-methoxy-1-methylpyrrolidin-2-yl)cyclopropoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-(dimethylamino)but-2-enyl yl)piperazin-2-yl)acetonitrile; 149. 2-((2S)-4-(2-(2-(dimethylamino)cyclopropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 150. 2-((2S)-1-((E)-But-2-enyl)-4-(2-(2-((dimethylamino)methyl)cyclopropoxy)-7-( 8-Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 151. 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclopropyl)methoxy)-7-(naphthalen-1-yl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 152. 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-fluorophenyl)-2-((2-((dimethylamino)methyl)cyclopropyl) methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 153. 2-((2S)-1-Propenyl-4-(2-((1R)-1-(2-(pyrrolidin-1-ylmethyl)cyclopropyl)ethoxy)-7-( o-Tolyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 154. 2-((2S)-1-Propenyl-4-(7-(3-fluoro-2-methylphenyl)-2-((1R)-1-(2-((1-methylpyrrole Alk-2-yl)methyl)cyclopropyl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl) Acetonitrile; 155. (S)-2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-(1-(pyrrolidin-1-ylmethyl)cyclobutoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 156. 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(1-((1-methylpyrrolidine-2 -yl)methyl)cyclobutoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 157. 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(1-(1-methylpyrrolidine-2- yl)cyclobutoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 158. 2-((2S)-1-Propenyl-4-(2-(2-(dimethylamino)cyclobutoxy)-7-(2-(trifluoromethyl)phenyl)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 159. (S)-2-(1-Propenyl-4-(2-(3-(ethyl(methyl)amino)cyclobutoxy)-7-(naphthalen-1-yl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 160. (S)-2-(1-Propenyl-4-(2-(3-(ethyl(2-methoxyethyl)amino)cyclobutoxy)-7-(naphthalen-1-yl) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 161. 2-((2S)-1-Propenyl-4-(2-(3-(dimethylamino)-2-(2-methoxyethyl)cyclobutoxy)-7-(naphthalene- 1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 162. (S)-2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-(3-(pyrrolidin-1-yl)cyclobutoxy)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 163. (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(pyrrolidin-1-yl)cyclobutyl)methoxy)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 164. 2-((2S)-1-Propenyl-4-(2-((1-(1-methylpyrrolidin-3-yl)cyclobutyl)methoxy)-7-(2-(tri Fluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 165. 2-((2S)-1-Propenyl-4-(2-((1-(1-methylpyrrolidin-2-yl)cyclobutyl)methoxy)-7-(2-(tri Fluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 166. 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclobutyl)methoxy)-7-(naphthalen-1-yl)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 167. (S)-2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((3-(dimethylamino)cyclobutyl) )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 168. 2-((S)-1-Propenyl-4-(2-((R)-1-(3-(dimethylamino)cyclobutyl)ethoxy)-7-(3-fluoro- 2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 169. (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)cyclopentyl)methoxy)-5,6 ,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 170. 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)-3-(trifluoromethyl)cyclopentyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 171. 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)-3-(trifluoromethoxy)cyclopentane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 172. 3-(((4-((S)-4-Propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)cyclopentane-1-carbonitrile; 173. Ethyl 3-(((4-((S)-4-propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)cyclopentane-1-carboxylate; 174. 3-(((4-((S)-4-Propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)-N,N-dimethylcyclopentane-1-carboxamide ; 175. 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)-3-(pyrrolidine-1-carboxy) ring pentyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 176. 3-(((4-((S)-4-Propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)-N-methylcyclopentane-1-carboxamide; 177. 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)-3-(thiazol-2-yl)cyclopentane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 178. (S)-2-(1-Propenyl-4-(7-(2,3-difluorophenyl)-2-((1-(pyrrolidin-1-yl)cyclopentyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 179. 2-((2S)-1-Propenyl-4-(2-((1-(1-methylpyrrolidin-2-yl)cyclopentyl)methoxy)-7-(naphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 180. 2-((2S)-1-Propenyl-4-(7-(2-chloro-3-fluorophenyl)-2-((2,2-difluoro-1-(1-methylpyrrolidine) -2-yl)cyclopentyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 181. 2-((2S)-1-Propenyl-4-(7-(2-chloro-3-fluorophenyl)-2-((1-(1-methylpyrrolidin-3-yl)cyclopentan yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 182. 2-((2S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((1-(1-isopropylpyrrolidin-3-yl)cyclopentane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 183. (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-((dimethylamino)methyl)cyclopentyl)oxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 184. (S)-2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopentyl)oxy)-7-(2-(tri Fluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 185. (S)-2-(1-Propenyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl) )cyclopentyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 186. 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((1-methylpyrrolidine- 2-yl)methyl)cyclopentyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 187. 2-((2S)-1-Propenyl-4-(2-((1-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)cyclopentyl)oxy yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 188. 2-((2S)-1-Propenyl-4-(2-((1-(difluoro(1-methylpyrrolidin-2-yl)methyl)cyclopentyl)oxy)-7- (3-Methyl-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl) Acetonitrile; 189. 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)oxy)-7-(3-methyl-2-(trifluoromethyl) yl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 190. 2-((2S)-1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)oxy)-7-(3-methyl-2-(trifluoromethyl) yl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 191. 2-((2S)-1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)methoxy)-7-(3-methyl-2-(trifluoro) methyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 192. 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(3-methyl-2-(trifluoro) methyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 193. (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-((dimethylamino)methyl)cyclohexyl)oxy)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 194. (S)-2-(1-Propenyl-4-(2-((1-(pyrrolidin-1-ylmethyl)cyclohexyl)oxy)-7-(2-(trifluoromethyl) phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 195. 2-((2S)-1-Propenyl-4-(7-(2-chloro-3-fluorophenyl)-2-((2-(dimethylamino)cyclohexyl)oxy)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 196. 2-((2S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((2-(1-methylazetidin-2-yl) cyclohexyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 197. 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((2-(dimethylamino)cyclohexyl) methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 198. 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclohexyl)methoxy)-7-(naphthalen-1-yl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 199. (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)cyclohexyl)methoxy)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 200. (S)-2-(1-Propenyl-4-(7-(2,3-difluorophenyl)-2-((1-((dimethylamino)methyl)cyclohexyl)methoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 201. (S)-2-(1-Propenyl-4-(2-((4-(dimethylamino)cyclohexyl)methoxy)-7-(naphthalen-1-yl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 202. 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((2-(pyrrolidin-1-yl)cycle) hexyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 203. 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((3-(dimethylamino)cyclohexyl) methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 204. 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((3-(dimethylamino)cyclohexyl) oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 205. N-(3-(((4-((S)-4-propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)cyclopentyl)acetamide; 206. 3-(((4-((S)-4-Propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)-N,N-dimethylcyclopentane-1-sulfonamide ; 207. 2-((2S)-1-Propenyl-4-(2-(((2-(dimethylamino)cyclobutyl)methyl)sulfanyl)-7-(naphthalen-1-yl)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; or 208. 2-((2S)-1-Propenyl-4-(2-(((2-(dimethylamino)cyclobutyl)methyl)amino)-7-(naphthalen-1-yl)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.

另一方面，提供藥物組合物，其包含本發明的至少一種式I的化合物，其藥學上可接受的鹽或其立體異構體，及至少一種藥學上可接受的賦形劑。In another aspect, there is provided a pharmaceutical composition comprising at least one compound of formula I of the present invention, a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

在一些實施方式中，所述的化合物與所述的賦形劑的重量比的範圍從約0.0001至約10。In some embodiments, the weight ratio of the compound to the excipient ranges from about 0.0001 to about 10.

在一些實施方式中，所述的化合物與所述的賦形劑的重量比的範圍從約0.01至約0.8。In some embodiments, the weight ratio of the compound to the excipient ranges from about 0.01 to about 0.8.

在一些實施方式中，所述的化合物與所述的賦形劑的重量比的範圍從約0.02至約0.2。In some embodiments, the weight ratio of the compound to the excipient ranges from about 0.02 to about 0.2.

在一些實施方式中，所述的化合物與所述的賦形劑的重量比的範圍從約0.05至約0.15。In some embodiments, the weight ratio of the compound to the excipient ranges from about 0.05 to about 0.15.

另一方面，提供本發明的式I的化合物、其藥學上可接受的鹽或其立體異構體；或本發明的所述藥物組合物在製備治療與KRAS突變蛋白相關的疾病或病症的藥物中的應用。In another aspect, there is provided a compound of formula I of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof; or the pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment of a disease or disorder associated with KRAS muteins applications in .

在一些實施方式中，其中所述的與KRAS突變蛋白相關的疾病或病症是與KRAS G12C突變蛋白相關的疾病或病症。In some embodiments, wherein the disease or disorder associated with the KRAS mutein is a disease or disorder associated with the KRAS G12C mutein.

在一些實施方式中，所述的與KRAS突變蛋白相關的疾病或病症是癌症。In some embodiments, the disease or disorder associated with a KRAS mutant protein is cancer.

在一些實施方式中，所述的癌症選自血液癌、胰腺癌、結腸癌、直腸癌、結直腸癌或肺癌。In some embodiments, the cancer is selected from blood cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or lung cancer.

在一些實施方式中，所述的血液癌選自急性髓性白血病或急性淋巴細胞白血病；所述的肺癌選自非小細胞肺癌或小細胞肺癌。In some embodiments, the blood cancer is selected from acute myeloid leukemia or acute lymphoblastic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

另一方面，提供一種治療患有與KRAS突變蛋白相關的疾病或病症的受體的方法，所述方法包括向所述受體給予治療有效量的至少一種本發明的式I的化合物、其藥學上可接受的鹽或其立體異構體；或本發明的所述藥物組合物。In another aspect, there is provided a method of treating a receptor suffering from a disease or disorder associated with a KRAS mutein, the method comprising administering to the receptor a therapeutically effective amount of at least one compound of formula I of the present invention, a pharmacy thereof an acceptable salt or a stereoisomer thereof; or the pharmaceutical composition of the present invention.

在一些實施方式中，所述的與KRAS突變蛋白相關的疾病或病症是與KRAS G12C突變蛋白相關的疾病或病症。In some embodiments, the disease or disorder associated with the KRAS mutein is a disease or disorder associated with the KRAS G12C mutein.

在一些實施方式中，所述的與KRAS突變蛋白相關的疾病或病症是癌症。In some embodiments, the disease or disorder associated with a KRAS mutant protein is cancer.

在一些實施方式中，所述的癌症選自血液癌、胰腺癌、結腸癌、直腸癌、結直腸癌或肺癌。In some embodiments, the cancer is selected from blood cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or lung cancer.

在一些實施方式中，所述的血液癌選自急性髓性白血病或急性淋巴細胞白血病；所述的肺癌選自非小細胞肺癌或小細胞肺癌。In some embodiments, the blood cancer is selected from acute myeloid leukemia or acute lymphoblastic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

定義definition

除非另有說明，本文所用的術語「鹵素」是指氟、氯、溴或碘。優選的鹵素基團包括F、Cl和Br。Unless otherwise indicated, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups include F, Cl and Br.

除非另有說明，本文所用的術語「烷基」包括具有直鏈或支鏈的飽和一價烷基。例如，烷基包括甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基和環己基。類似地，C1-6 烷基中的C1-6 被定義為直鏈或支鏈排列中該基團具有1、2、3、4、5或6個碳原子。Unless otherwise specified, the term "alkyl" as used herein includes saturated monovalent alkyl groups having straight or branched chains. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl , 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C 1-6 alkyl C 1-6 is defined as having 1,2,3,4,5 or 6 carbon atoms, a straight-chain or branched-chain arrangement of the group.

術語「亞烷基」是指通過從如上定義的烷基除去氫原子而獲得的雙官能團。例如，亞甲基（即-CH2 -）、亞乙基（即-CH2 -CH2 -或-CH(CH3 )-）和亞丙基（即-CH2 -CH2 -CH2 -、-CH(-CH2 -CH3 ))-或-CH2 -CH(CH3 )-）。The term "alkylene" refers to a bifunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, methylene (ie -CH 2 -), ethylene (ie -CH 2 -CH 2 - or -CH(CH 3 )-) and propylene (ie -CH 2 -CH 2 -CH 2 - , -CH(-CH 2 -CH 3 ))- or -CH 2 -CH(CH 3 )-).

術語「烯基」是指含有一個或多個雙鍵且通常長度為2至20個碳原子的直鏈或支鏈烴基。例如，「C2-6 鏈烯基」含有2至6個碳原子。烯基包括但不限於例如乙烯基、丙烯基、丁烯基、2-甲基-2-丁烯-1-基、庚烯基、辛烯基等。The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms in length. For example, "C 2-6 alkenyl" contains 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

術語「炔基」含有一個或多個三鍵並且通常長度為2至20個碳原子的直鏈或支鏈烴基。例如，「C2-6 炔基」含有2至6個碳原子。代表性的炔基包括但不限於，例如，乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。The term "alkynyl" contains one or more triple bonds and is usually a straight or branched chain hydrocarbon group of 2 to 20 carbon atoms in length. For example, "C 2-6 alkynyl" contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

術語「烷氧基」基團是由前述烷基形成的氧醚。The term "alkoxy" group is an oxygen ether formed from the aforementioned alkyl groups.

除非另有說明，本文所用的術語「芳基」是指含有碳環原子的未取代或取代的單環或多環芳環系統。優選的芳基是單環或雙環6-10元芳環系統。苯基和萘基是優選的芳基。最優選的芳基是苯基。Unless otherwise indicated, the term "aryl" as used herein refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

除非另有說明，本文所用的術語「雜環基」或「雜環」是指含有一個或多個雜原子的未取代和取代的單環或多環非芳族環系。優選的雜原子包括N、O和S，包括N-氧化物、硫氧化物和二氧化物。優選地，該環是三至八元並且是完全飽和的或具有一個或多個不飽和度。本定義包括多個取代度，優選一個、兩個或三個取代度。The terms "heterocyclyl" or "heterocycle" as used herein, unless otherwise specified, refer to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms. Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides and dioxides. Preferably, the ring is three to eight membered and is fully saturated or has one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably one, two or three degrees of substitution.

這種雜環基的實例包括但不限於氮雜環丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、氧代氮雜環庚基、氮雜環庚基、四氫呋喃基、二氧戊環基、四氫咪唑基、四氫噻唑基、四氫

Figure 02_image1249
唑基、四氫吡喃基、嗎福林基、硫代嗎福林基、硫代嗎福林基亞碸、硫代嗎福林基碸和
Figure 02_image1249
二唑基。Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, oxoazepanyl, Azacycloheptyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydro
Figure 02_image1249
azolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl and
Figure 02_image1249
oxadiazolyl.

除非另有說明，本文所用的術語「雜芳基」表示含有碳和至少一個雜原子的芳環系統。雜芳基可以是單環的或多環的，取代的或未取代的，本發明中所述雜芳基的兩個相鄰的取代基可形成本發明中所定義的C3-6 碳環或C3-6 雜環。單環雜芳基在環中可具有1至4個雜原子，而多環雜芳基可包含1至10個雜原子。多環雜芳基環可含有稠合、螺環或橋環結合，例如，雙環雜芳基是多環雜芳基。雙環雜芳基環可含有8至12個成員原子。單環雜芳基環可含有5至8個成員原子（碳原子和雜原子）。雜芳基的實例包括，但不限於噻吩基、呋喃基、咪唑基、異

Figure 02_image1249
唑基、
Figure 02_image1249
唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、噠嗪基、吲哚基、氮雜吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并異
Figure 02_image1249
唑基、苯并
Figure 02_image1249
唑基、苯并吡唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基、腺嘌呤基、喹啉基或異喹啉基。Unless otherwise specified, the term "heteroaryl" as used herein refers to an aromatic ring system containing carbon and at least one heteroatom. The heteroaryl group can be monocyclic or polycyclic, substituted or unsubstituted, and two adjacent substituents of the heteroaryl group in the present invention can form a C 3-6 carbocyclic ring as defined in the present invention or C 3-6 heterocycle. Monocyclic heteroaryl groups can have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings may contain fused, spiro or bridged ring linkages, eg, a bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, iso
Figure 02_image1249
azolyl,
Figure 02_image1249
azolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzo furanyl, benzothienyl, benziso
Figure 02_image1249
azolyl, benzoyl
Figure 02_image1249
azolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl or isoquinolinyl.

術語「碳環」是指取代或未取代的單環、雙環或多環非芳族飽和環，其任選地包括亞烷基連接基，環烷基可通過該亞烷基連接基連接。示例性的「環烷基」基團包括但不限於環丙基、環丁基、環戊基、環己基等。The term "carbocycle" refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring that optionally includes an alkylene linker through which a cycloalkyl group can be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

術語「氧代」是指氧與所連接的碳原子一起形成

Figure 02_image1251
基團。The term "oxo" refers to the formation of oxygen together with the carbon atom to which it is attached
Figure 02_image1251
group.

術語「羧基」是指基團C(O)OH。The term "carboxy" refers to the group C(O)OH.

術語「-C1-6 亞烷基-C6-10 芳基」是指被如上定義的C6-10 芳基取代的-C1-6 烷基。The term "-C 1-6 alkylene-C 6-10 aryl" refers to -C 1-6 alkyl substituted with C 6-10 aryl as defined above.

術語「-C1-6 亞烷基-(5-10元雜芳基)」是指被如上定義的5-10元雜芳基取代的-C1-6 烷基。The term "-C 1-6 alkylene-(5-10 membered heteroaryl)" refers to -C 1-6 alkyl substituted with a 5-10 membered heteroaryl group as defined above.

術語「-C1-6 亞烷基-(3-10元雜環基)」是指被如上定義的3-10元雜環基取代的-C1-6 烷基。The term "-C 1-6 alkylene-(3-10 membered heterocyclyl)" refers to -C 1-6 alkyl substituted with a 3-10 membered heterocyclyl group as defined above.

術語「-C1-6 亞烷基-C3-10 碳環基」是指被如上定義的C3-10 碳環基取代的-C1-6 烷基。The term "-C 1-6 alkylene-C 3-10 carbocyclyl" refers to a -C 1-6 alkyl group substituted with a C 3-10 carbocyclyl group as defined above.

術語「-C1-6 亞烷基-(鹵素)1-3 」是指被1、2或3個如上定義的鹵素取代的-C1-6 烷基。The term "-C 1-6 alkylene-(halogen) 1-3 " refers to -C 1-6 alkyl substituted with 1, 2 or 3 halogens as defined above.

術語「C1-6 雜烷基」是指如上定義的-C1-6 烷基的鏈中的一個或多個碳原子被選自O、S或N的雜原子所替代後的基團。The term "C 1-6 heteroalkyl" refers to a group as defined above in which one or more carbon atoms in the chain of -C 1-6 alkyl have been replaced by a heteroatom selected from O, S or N.

術語「-C1-6 亞烷基-(OR8 )1-3 」是指被1、2或3個OR8 取代的-C1-6 烷基，其中R8 的定義如上所述，優選的R8 選自氫、甲基、乙基或丙基。The term "-C 1-6 alkylene-(OR 8 ) 1-3 " refers to -C 1-6 alkyl substituted with 1, 2 or 3 OR 8 , wherein R 8 is as defined above, preferably The R 8 is selected from hydrogen, methyl, ethyl or propyl.

術語「-O-C1-6 亞烷基-(鹵素)1-3 」是指如上定義的-C1-6 亞烷基-(鹵素)1-3 的氧醚。The term "-OC 1-6 alkylene-(halogen) 1-3 " refers to the oxyether of -C 1-6 alkylene-(halogen) 1-3 as defined above.

術語「-S-C1-6 亞烷基-(鹵素)1-3 」是指如上定義的-C1-6 亞烷基-(鹵素)1-3 的S醚。The term "-SC 1-6 alkylene-(halogen) 1-3 " refers to the S ether of -C 1-6 alkylene-(halogen) 1-3 as defined above.

術語「-C1-6 亞烷基-NR8 R9 」是指被-NR8 R9 取代的-C1-6 烷基，其中所述的R8 和R9 的定義如上所述。The term "-C 1-6 alkylene-NR 8 R 9 " refers to -C 1-6 alkyl substituted with -NR 8 R 9 , wherein said R 8 and R 9 are as defined above.

術語「-C1-6 亞烷基-C(=O)NR8 R9 」是指被-C(=O)NR8 R9 取代的-C1-6 烷基，其中所述的R8 和R9 的定義如上所述。The term "-C 1-6 alkylene-C(=O)NR 8 R 9 " refers to -C 1-6 alkyl substituted by -C(=O)NR 8 R 9 , wherein said R 8 and R 9 is defined above.

術語「-C1-6 亞烷基-NR8 C(=O)R8 」是指被-NR8 C(=O)R8 取代的-C1-6 烷基。The term "-C 1-6 alkylene-NR 8 C(=O)R 8 " refers to -C 1-6 alkyl substituted with -NR 8 C(=O)R 8 .

術語「-C1-6 亞烷基-CN」是指被-CN取代的-C1-6 烷基。The term "-C 1-6 alkylene-CN" refers to a -C 1-6 alkyl group substituted with -CN.

如本文所用，術語「組合物」旨在涵蓋包含特定量的特定成分的產品，以及直接或間接由特定量的特定成分的組合產生的任何產品。因此，含有本發明化合物作為活性成分的藥物組合物以及製備本發明化合物的方法也是本發明的一部分。As used herein, the term "composition" is intended to encompass products comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention.

本發明化合物也可以藥學上可接受的鹽的形式存在。對於在醫藥中使用，本發明化合物的鹽是指無毒的「藥學上可接受的鹽」。本發明在其範圍內包括本發明化合物的前藥。通常，這種前藥是化合物的功能性衍生物，其易於在體內轉化為所需化合物。因此，在本發明的治療方法中，術語「給藥」應包括用特定公開的化合物，或用可能未具體公開的化合物，但給予受試者後在體內轉化為特定化合物的化合物治療描述的各種病症。用於選擇和製備合適的前藥衍生物的常規方法描述於例如「前藥設計」（「Design of Prodrugs」, ed. H. Bundgaard, Elsevier, 1985.）。The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". The present invention includes within its scope prodrugs of the compounds of the present invention. Typically, such prodrugs are functional derivatives of compounds that are readily converted to the desired compound in vivo. Thus, in the methods of treatment of the present invention, the term "administration" shall include treatment of the various described compounds with a specifically disclosed compound, or with a compound that may not be specifically disclosed, but which upon administration to a subject converts to the specified compound in vivo disease. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs" ("Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.).

分子中特定位置的任何取代基或變量的定義旨在獨立於該分子中其他位置的取代基或變量的定義。應當理解，本領域普通通常知識者可以選擇本發明化合物上的取代基和取代模式，以提供化學穩定的化合物，並且可以通過本領域已知的技術以及本文闡明的方法容易地合成。The definition of any substituent or variable at a particular position in a molecule is intended to be independent of the definition of substituents or variables at other positions in that molecule. It will be appreciated that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide chemically stable compounds that can be readily synthesized by techniques known in the art and by the methods set forth herein.

本發明包括所述化合物可含有一個或多個不對稱中心，因此可產生非對映異構體和光學異構體。本發明包括所有這些可能的非對映異構體及其外消旋混合物、它們基本上純的拆分的對映異構體、所有可能的幾何異構體、及其藥學上可接受的鹽。The present invention contemplates that the compounds may contain one or more asymmetric centers and thus may give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof .

本發明包括化合物的所有立體異構體及其藥學上可接受的鹽。此外，還包括立體異構體的混合物以及分離的特定立體異構體。在用於製備這些化合物的合成方法的過程中，或在使用本領域通常知識者已知的外消旋化或差向異構化方法的過程中，這些方法的產物可以是立體異構體的混合物。The present invention includes all stereoisomers of the compounds and their pharmaceutically acceptable salts. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic methods used to prepare these compounds, or during the use of racemization or epimerization methods known to those of ordinary skill in the art, the products of these methods may be stereoisomers mixture.

本發明所述「立體異構體」是指分子中原子或原子團互相連接次序相同，但空間排列不同而引起的異構體，其包括構型異構體和構象異構體，其中的構型異構體又包括幾何異構體和旋光異構體，旋光異構體主要包括對映異構體和非對映異構體。The term "stereoisomers" in the present invention refers to isomers caused by atoms or atomic groups in the molecule in the same order of interconnection, but with different spatial arrangements, including configurational isomers and conformational isomers. Isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.

本發明旨在包括本發明化合物中存在的所有原子同位素。同位素是具有相同原子序數但質量數不同的原子。作為一般實例而非限制，氫的同位素包括氘和氚。氫的同位素可表示為1 H（氫），2 H（氘）和3 H（氚）。它們通常也表示為D（氘）和T（氚）。在本申請中，CD3 表示甲基，其中所有氫原子都是氘。碳的同位素包括13 C和14 C。本發明的同位素標記的化合物通常可以通過本領域通常知識者已知的常規技術或通過與本文所述類似的方法製備，使用適當的同位素標記的試劑代替非標記試劑。The present invention is intended to include all atomic isotopes present in the compounds of the present invention. Isotopes are atoms with the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). They are also commonly denoted D (deuterium) and T (tritium). In this application, CD 3 represents a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon include 13 C and 14 C. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those of ordinary skill in the art or by methods analogous to those described herein, using the appropriate isotopically-labeled reagent in place of the non-labeled reagent.

除非另有說明，當式I化合物的互變異構體存在時，本發明包括任何可能的互變異構體及其藥學上可接受的鹽，以及它們的混合物。Unless otherwise indicated, when tautomers of compounds of formula I exist, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, as well as mixtures thereof.

當式I化合物及其藥學上可接受的鹽以溶劑化物或多晶型形式存在時，本發明包括任何可能的溶劑化物和多晶型。形成溶劑化物的溶劑的類型沒有特別限制，只要溶劑是藥理學上可接受的即可。例如，可以使用水、乙醇、丙醇、丙酮等。When the compounds of formula I and pharmaceutically acceptable salts thereof exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and the like can be used.

本發明的藥物組合物包含式I代表的化合物（或其藥學上可接受的鹽）作為活性成分，藥學上可接受的載體和任選的其它佐劑。儘管在任何給定情況下最合適的途徑將取決於特定的宿主，以及為病症（為治療該病症而正在施用該活性成分）的性質和嚴重程度，但該組合物包括適於口服、直腸、局部和腸胃外（包括皮下、肌肉內和靜脈內）給藥的組合物。藥物組合物可以方便地以單位劑型存在，並通過藥學領域熟知的任何方法製備。The pharmaceutical composition of the present invention comprises a compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other adjuvants. Although the most appropriate route in any given situation will depend on the particular host, as well as the nature and severity of the condition for which the active ingredient is being administered, the compositions include oral, rectal, Compositions for topical and parenteral (including subcutaneous, intramuscular and intravenous) administration. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

在實踐中，根據常規藥物配製技術，本發明的式I代表的化合物或其前藥或代謝物或其藥學上可接受的鹽可以作為活性成分與藥物載體組合成緊密混合物。載體可以採取多種形式，這取決於給藥途徑所需的製劑形式，例如口服或腸胃外（包括靜脈內）給藥途徑。因此，本發明的藥物組合物可以作為適於口服給藥的離散單位存在，例如每個含有預定量的活性成分的膠囊、扁囊劑（cachets）或片劑。此外，組合物可以粉末形式、顆粒形式、溶液形式、水性液體中的懸浮液、非水液體、水包油乳液或油包水乳液形式存在。除了上述常見劑型外，式I代表的化合物或其藥學上可接受的鹽還可以通過控釋裝置和/或遞送裝置給藥。該組合物可以通過任何藥學方法製備。通常，這些方法包括使活性成分與構成一種或多種必需成分的載體結合的步驟。通常，通過將活性成分與液體載體或細碎的固體載體或兩者均勻且緊密地混合來製備組合物。然後可以方便地將產品成形為所需的樣式。In practice, the compounds represented by formula I of the present invention, or prodrugs or metabolites thereof, or pharmaceutically acceptable salts thereof, can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier may take a variety of forms, depending on the desired form of formulation for the route of administration, eg, oral or parenteral (including intravenous) routes of administration. Accordingly, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration, such as capsules, cachets or tablets each containing a predetermined quantity of the active ingredient. In addition, the compositions may exist in powder form, granular form, solution form, suspension in aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition to the common dosage forms described above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, can also be administered by controlled release devices and/or delivery devices. The composition can be prepared by any method of pharmacy. Generally, these methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both. The product can then be conveniently shaped into the desired style.

因此，本發明的藥物組合物可包括藥學上可接受的載體和式I的化合物或藥學上可接受的鹽。Accordingly, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt.

所用的藥物載體可以例如是固體、液體或氣體。固體載體的實例包括乳糖、石膏粉、蔗糖、滑石粉、明膠、瓊脂、果膠、阿拉伯膠、硬脂酸鎂和硬脂酸。液體載體的實例是糖漿、花生油、橄欖油和水。氣態載體的實例包括二氧化碳和氮氣。在製備用於口服劑型的組合物中，可以使用任何方便的藥物介質。例如，水、乙二醇、油、醇、調味劑、防腐劑、著色劑等可被用於形成例如懸浮液、酏劑和溶液的口服液體製劑；而澱粉、糖、微晶纖維素、稀釋劑、造粒劑、潤滑劑、粘合劑、崩解劑等載體可被用於形成如粉末、膠囊和片劑的口服固體製劑。由於易於給藥，片劑和膠囊是優選的口服劑量單位，其中使用固體藥物載體。任選地，片劑可以通過標準水性或非水性技術包衣。The pharmaceutical carrier used can be, for example, solid, liquid or gaseous. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like can be used to form oral liquid preparations such as suspensions, elixirs, and solutions; while starch, sugar, microcrystalline cellulose, dilute Carriers such as agents, granulating agents, lubricants, binders, disintegrating agents, etc., can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units in which solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or non-aqueous techniques.

含有本發明組合物的片劑可以通過壓製或模塑製備，任選地含有一種或多種輔助成分或佐劑。壓縮片劑可以通過在合適的機器中壓製如粉末或顆粒自由流動形式的活性成分，任選地與粘合劑、潤滑劑、惰性稀釋劑、表面活性劑或分散劑混合來製備。模製片劑可以通過在合適的機器中模製用惰性液體稀釋劑潤濕的粉末化合物的混合物來製備。每片優選含有約0.05mg至約5g活性成分，每個扁囊劑或膠囊優選含有約0.05mg至約5g活性成分。例如，用於人口服給藥的製劑可含有與適當和方便量的載體物質混合的約0.5mg至約5g活性劑，載體物質可占總組合物的約0.05％至約95％。單位劑型通常含有約0.01mg至約2g活性成分，通常0.01mg、0.02mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、25mg、50mg、 100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。Tablets containing the compositions of the present invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, formulations for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent in admixture with a suitable and convenient amount of carrier material, which may comprise from about 0.05% to about 95% of the total composition. A unit dosage form typically contains from about 0.01 mg to about 2 g of active ingredient, usually 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400mg, 500mg, 600mg, 800mg or 1000mg.

適合腸胃外給藥的本發明藥物組合物可以製備成活性化合物在水中的溶液或懸浮液。可以包括合適的表面活性劑，例如羥丙基纖維素。分散體也可以在甘油、液體聚乙二醇及其在油中的混合物中製備。此外，可以包含防腐劑以防止微生物的有害生長。Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. Suitable surfactants such as hydroxypropyl cellulose may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, preservatives may be included to prevent harmful growth of microorganisms.

適用於注射用途的本發明藥物組合物包括無菌水溶液或分散液。此外，組合物可以是用於臨時製備這種無菌可注射溶液或分散體的無菌粉末的形式。在所有情況下，最終的可注射形式必須是無菌的並且必須是有效流動的以便於注射。藥物組合物在製造和儲存條件下必須是穩定的；因此，優選應該防止如細菌和真菌的微生物的污染下保藏。載體可以是例如含有水、乙醇、多元醇（例如甘油、丙二醇和液體聚乙二醇）、植物油及其合適的混合物的溶劑或分散介質。Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Additionally, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be fluid for easy injection. Pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, they should preferably be preserved against contamination by microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

本發明的藥物組合物可以是適於局部使用的形式，例如氣溶膠、乳膏、軟膏、洗劑、撒粉等。此外，組合物可以是適用於透皮裝置的形式。利用本發明的式I化合物或其藥學上可接受的鹽，這些製劑可以通過常規加工方法來製備。例如，通過將親水性材料和水與約0.05wt％至約10wt％的化合物混合以產生具有所需稠度的乳膏或軟膏來製備乳膏或軟膏。The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, and the like. Furthermore, the compositions may be in a form suitable for use in transdermal devices. These formulations can be prepared by conventional processing methods utilizing a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 0.05% to about 10% by weight of the compound to produce a cream or ointment of the desired consistency.

本發明的藥物組合物可以是適於直腸給藥的形式，其中載體是固體。優選混合物形成單位劑量栓劑。合適的載體包括可可脂和本領域常用的其他材料。栓劑可以通過首先將組合物與軟化或熔化的載體混合，然後在模具中冷卻和成型來方便地形成。The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably the mixture is formed into a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with a softened or molten carrier, then cooling and shaping in a mold.

除了上述載體成分之外，上述藥物製劑可以適當地包括一種或多種另外的載體成分，例如稀釋劑、緩衝劑、調味劑、粘合劑、表面活性劑、增稠劑、潤滑劑、防腐劑（包括抗氧化劑）等等。此外，可以包括其他佐劑以使製劑與預期接受者的血液等滲。含有式I所示化合物或其藥學上可接受的鹽的組合物也可以製備成粉末或液體濃縮物形式。In addition to the aforementioned carrier ingredients, the aforementioned pharmaceutical formulations may suitably include one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surfactants, thickening agents, lubricants, preservatives ( including antioxidants), etc. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of Formula I, or a pharmaceutically acceptable salt thereof, can also be prepared in the form of powders or liquid concentrates.

通常，每天約0.001mg/kg至約150mg/kg體重的劑量水平可用於治療上述病症，或者每位患者每天約0.05mg至約7g。Typically, dosage levels of about 0.001 mg/kg to about 150 mg/kg of body weight per day can be used to treat the above-mentioned conditions, or about 0.05 mg to about 7 g per patient per day.

然而，應理解，任何特定患者的具體劑量水平將取決於包括年齡、體重、一般健康狀況、性別、飲食、給藥時間、給藥途徑、排泄率、藥物組合以及接受治療的特定疾病的嚴重程度的多種因素。It is to be understood, however, that the specific dosage level for any particular patient will depend on factors including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease being treated. of multiple factors.

從以下對本發明的書面描述中，這些和其他方面將變得顯而易見。These and other aspects will become apparent from the following written description of the invention.

反應路線reaction route

式（I）化合物可以使用本文所述的合成方法和反應方案由市售試劑製備，或使用本領域通常知識者眾所周知的其他試劑和常規方法製備。Compounds of formula (I) can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those of ordinary skill in the art.

例如，本發明的化合物可以根據如下的通用反應方案製備：

Figure 02_image1253
For example, compounds of the present invention can be prepared according to the following general reaction scheme:
Figure 02_image1253

在步驟A中，所述的取代基

Figure 02_image1255
可以通過親核試劑（例如在溶劑中（如THF）的反-4-(二甲基氨基)環己烷）取代氯引入來獲得化合物(2)；或者
Figure 02_image1255
可以通過與化合物（1）的鈀催化偶聯引入，例如在存在鈀催化劑（如Pd2 (dba)3 /BINAP）的溶劑中（如甲苯）使用鹼（如碳酸銫或第三丁醇鈉）來合成化合物(2)。In step A, the substituents
Figure 02_image1255
Compound (2) can be obtained by introduction of a nucleophile such as trans-4-(dimethylamino)cyclohexane in a solvent such as THF in place of chlorine; or
Figure 02_image1255
By palladium catalyzed coupling of the compound (1) is introduced, a palladium catalyst, for example a solvent (e.g., Pd 2 (dba) 3 / BINAP ) in (such as toluene) using a base (such as cesium carbonate or sodium tert-butanol) in the presence of to synthesize compound (2).

在步驟B中，使用本領域熟知的條件脫去苄基，例如使用Pd/C在存在H2 的極性溶劑中（如甲醇）的氫化反應來提供化合物（3）。In Step B, using conditions known in the art debenzylated, for example using Pd / C to provide the compound (3) of H 2 in a polar solvent (such as methanol) in the presence of a hydrogenation reaction.

在步驟C中，在鈀催化劑（例如Pd2 (dba)3 /Ruphos）的存在下，在合適的溶劑（如甲苯）中，採用鹼（如碳酸銫），使用合適的官能化的芳基或雜芳基體系，通過鈀催化偶聯引入取代基「-L1 -R1 」。來提供化合物（4）。In Step C, in the presence of a palladium catalyst (e.g., Pd 2 (dba) 3 / Ruphos ) in a suitable solvent (such as toluene) using a base (such as cesium carbonate), using a suitable functionalized aryl group or Heteroaryl system, the substituent "-L 1 -R 1 " is introduced by palladium-catalyzed coupling. to provide compound (4).

在步驟D中，使用本領域熟知的條件脫去L4 的保護劑，例如使用在溶劑（如二氯甲烷）中的三氟乙酸來提供化合物（5）。In step D, using conditions known in the art protective agent L 4 is removed, for example in a solvent (such as dichloromethane) in trifluoroacetic acid to provide compound (5).

在步驟E中，引入R4 來提供式（I）的化合物，例如通過使用具有式Cl-C(O)-CR=CR的醯氯或具有式CR=CR-C(O)-O-C(O)-CR=CR的酸酐在溶劑（如二氯甲烷）存在下使用鹼（如Hunig 鹼）來提供式（I）的化合物。In step E, to provide a compound of formula is introduced (I), R 4, for example by using a formula Cl-C (O) -CR = CR or an acyl chloride of the formula CR = CR-C (O) -OC (O Anhydrides of )-CR=CR in the presence of a solvent such as dichloromethane using a base such as Hunig base to provide compounds of formula (I).

在一些情況下，R1 和

Figure 02_image1255
也可以含有保護基，這些保護基可以在合成的後續步驟中將其脫去。In some cases, R 1 and
Figure 02_image1255
Protecting groups may also be present which can be removed in subsequent steps of the synthesis.

實施例Example

提供下列實施例用於說明本發明。除非另有明確說明，所有份數和百分比均以重量計，所有的溫度均為攝氏度。示例中使用了以下縮寫： MeOH 甲醇 HATU 2-（7-氮雜苯并三氮唑）-N,N,N',N'-四甲基脲六氟磷酸酯 DCE 1,2-二氯乙烷 DBU 1,8-二氮雜二環十一碳-7-烯 Hex 正己烷 NaBH4 硼氫化鈉 THF 四氫呋喃 TFA 三氟乙酸 DMF N,N-二甲基甲醯胺 NaOMe 甲醇鈉 DCM 二氯甲烷 (Boc)2 O 二碳酸二第三丁酯 EtOAc 乙酸乙酯 t-BuONa 第三丁醇鈉 ACN 乙腈 m-CPBA 間氯過氧苯甲酸 TEA 三乙胺 K2 CO3 碳酸鉀 DIEA N,N-二異丙基乙胺 Na2 SO4 硫酸鈉 Pd2 (dba)3 三(二亞苄基丙酮)二鈀(0) min 分鐘 BINAP 2,2'-雙(二苯基膦)-1,1'-聯萘 h 小時 RuPhos 2-二環己基磷-2',6'-二異丙氧基-1,1'-聯苯 Pre-TLC 製備薄層色譜法 BOP 苯并三氮唑-1-基氧基三(二甲基氨基)磷六氟磷酸鹽       The following examples are provided to illustrate the invention. All parts and percentages are by weight and all temperatures are in degrees Celsius unless expressly stated otherwise. The following abbreviations are used in the examples: MeOH methanol HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate DCE 1,2-Dichloroethane DBU 1,8-Diazabicycloundec-7-ene Hex n-hexane NaBH 4 Sodium borohydride THF tetrahydrofuran TFA Trifluoroacetate DMF N,N-Dimethylformamide NaOMe Sodium methoxide DCM Dichloromethane (Boc) 2 O Di-tert-butyl dicarbonate EtOAc Ethyl acetate t-BuONa Sodium tertiary butoxide ACN Acetonitrile m-CPBA m-chloroperoxybenzoic acid TEA triethylamine K 2 CO 3 Potassium carbonate DIEA N,N-Diisopropylethylamine Na 2 SO 4 Sodium sulfate Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0) min minute BINAP 2,2'-Bis(diphenylphosphine)-1,1'-binaphthyl h Hour RuPhos 2-Dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl Pre-TLC Preparative Thin Layer Chromatography BOP Benzotriazol-1-yloxytris(dimethylamino)phosphorus hexafluorophosphate

中間體A1

Figure 02_image1259
以N-苄基-3-氧代哌啶-4-羧酸乙酯鹽酸鹽為起始物料，按照WO2017201161 A1所述步驟四步合成中間體A1Intermediate A1
Figure 02_image1259
Using N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride as the starting material, the intermediate A1 was synthesized in four steps according to the steps described in WO2017201161 A1

中間體A2

Figure 02_image1260
Intermediate A2
Figure 02_image1260

步驟a：室溫下，向中間體A2-01(59.46g，0.20mol)、S-甲基異硫脲半硫酸鹽(57.21 g, 0.30 mol, 0.5 H2 SO4 )和甲醇(800mL)的混合物中加入甲醇鈉(54.22g，1.00mol)。反應混合物於室溫下攪拌反應26小時。體系減壓濃縮。殘餘物分散於水(500mL)中，以濃鹽酸調pH=3～4。體系過濾，濾餅經真空乾燥得到淺棕色固體中間體A2-02(56.00g，0.19mol)。MS: m/z 288 [M+H]+ 。Step a: To a solution of Intermediate A2-01 (59.46g, 0.20mol), S- methylisothiourea hemisulfate (57.21 g, 0.30 mol, 0.5 H 2 SO 4) and methanol (800 mL) of To the mixture was added sodium methoxide (54.22 g, 1.00 mol). The reaction mixture was stirred at room temperature for 26 hours. The system was concentrated under reduced pressure. The residue was dispersed in water (500 mL) and adjusted to pH=3-4 with concentrated hydrochloric acid. The system was filtered, and the filter cake was dried under vacuum to obtain a light brown solid Intermediate A2-02 (56.00 g, 0.19 mol). MS: m/z 288 [M+H] + .

步驟b：向中間體A2-02(4.04 g，14.06 mmol)、2-哌嗪乙腈二鹽酸鹽(4.10g，50.70 mmol，2HCl)、BOP(8.00 g，18.09 mmol)和DMF(80mL)的溶液中加入DIEA(9.10 g，70.41 mmol)。體系升溫至70℃攪拌過夜。體系加入(Boc)2 O (9.30 g, 42.61 mmol)，室溫攪拌4小時。體系加水，並以乙酸乙酯萃取兩次。合併有機相，以飽和食鹽水洗滌，無水硫酸鈉乾燥、過濾、減壓濃縮。殘餘物以矽膠柱層析法純化(以Hex：EtOAc=50:1～2:1，v/v洗脫)，得到黃色固體中間體A2-03 (4.00 g, 8.09 mmol) MS: m/z 495 [M+H]+ 。Step b: To a mixture of Intermediate A2-02 (4.04 g, 14.06 mmol), 2-piperazineacetonitrile dihydrochloride (4.10 g, 50.70 mmol, 2HCl), BOP (8.00 g, 18.09 mmol) and DMF (80 mL) To the solution was added DIEA (9.10 g, 70.41 mmol). The system was warmed to 70°C and stirred overnight. (Boc) 2 O (9.30 g, 42.61 mmol) was added to the system, and the mixture was stirred at room temperature for 4 hours. Water was added to the system and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with Hex: EtOAc = 50: 1 ~ 2: 1, v/v) to give yellow solid Intermediate A2-03 (4.00 g, 8.09 mmol) MS: m/z 495 [M+H] + .

步驟c：於0℃下，向中間體A2-03 (4.00 g, 8.09 mmol) 和DIEA (3.15 g, 24.37 mmol)的DCE (100 mL)溶液中加入1-氯乙基氯甲酸酯(2.90 g, 20.28 mmol)。體系於室溫下攪拌4小時。反應混合物減壓濃縮。殘餘物溶於甲醇(400 mL)中，回流攪拌1.5小時。反應混合物減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM：MeOH=50:1～10:1，v/v洗脫)，得到粉色固體中間體A2 (3.15 g, 7.79 mmol)。MS: m/z 405 [M+H]+ 。Step c: To a solution of Intermediate A2-03 (4.00 g, 8.09 mmol) and DIEA (3.15 g, 24.37 mmol) in DCE (100 mL) at 0 °C was added 1-chloroethyl chloroformate (2.90 g, 20.28 mmol). The system was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (400 mL) and stirred at reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=50:1-10:1, v/v) to give Intermediate A2 (3.15 g, 7.79 mmol) as a pink solid. MS: m/z 405 [M+H] + .

中間體 A3

Figure 02_image1261
Intermediate A3
Figure 02_image1261

步驟a：向中間體A1-02 (43.89 g, 152.73 mmol)、(S)-2-(哌嗪-2-基)乙腈二鹽酸鹽(32.63 g, 164.72 mmol, 2HCl)和BOP (89.37 g, 202.07 mmol)的DMF(80 mL)溶液中加入DBU (134.82 g, 885.60 mmol)。體系於室溫攪拌40分鐘。向體系加入(Boc)2 O (68.84 g, 315.42 mmol)，升溫至40℃攪拌過夜。體系加水，並以乙酸乙酯萃取兩次。合併有機相，以飽和食鹽水洗滌，無水硫酸鈉乾燥、過濾、減壓濃縮。殘餘物以矽膠柱層析法純化(以Hex：EtOAc =50:1～2:1，v/v洗脫)，得到黃色固體中間體A3-01(43.59 g, 88.12 mmol)。MS: m/z 495 [M+H]+ 。Step a: To intermediate A1-02 (43.89 g, 152.73 mmol), (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (32.63 g, 164.72 mmol, 2HCl) and BOP (89.37 g , 202.07 mmol) in DMF (80 mL) was added DBU (134.82 g, 885.60 mmol). The system was stirred at room temperature for 40 minutes. (Boc) 2 O (68.84 g, 315.42 mmol) was added to the system, and the temperature was raised to 40° C. and stirred overnight. Water was added to the system and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with Hex: EtOAc = 50: 1-2: 1, v/v) to give intermediate A3-01 (43.59 g, 88.12 mmol) as a yellow solid. MS: m/z 495 [M+H] + .

步驟b：於0℃下，向中間體A3-01 (36.60 g, 73.99 mmol) 和DIEA (44.27 g, 342.54 mmol)的DCE (250 mL)溶液中加入1-氯乙基氯甲酸酯(39.54 g, 276.56 mmol)。體系於室溫下攪拌4小時。反應混合物減壓濃縮。殘餘物溶於甲醇(250 mL)中，回流攪拌1.5小時。反應混合物減壓濃縮。殘餘物分散於EtOAc (200mL)，10%檸檬酸溶液(150mL*2)萃取。水相以碳酸鉀固體調pH=12，以EtOAc (200mL*2)萃取，有機相以無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到中間體A3 (27.82 g)。MS: m/z 405 [M+H]+ 。Step b: To a solution of Intermediate A3-01 (36.60 g, 73.99 mmol) and DIEA (44.27 g, 342.54 mmol) in DCE (250 mL) at 0 °C was added 1-chloroethyl chloroformate (39.54 g g, 276.56 mmol). The system was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (250 mL) and stirred at reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dispersed in EtOAc (200 mL) and extracted with 10% citric acid solution (150 mL*2). The aqueous phase was adjusted to pH=12 with solid potassium carbonate, extracted with EtOAc (200 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate A3 (27.82 g). MS: m/z 405 [M+H] + .

中間體B1

Figure 02_image1262
Intermediate B1
Figure 02_image1262

步驟a:中間體B1-01 (2.11 g, 16.47 mmol)和二甲胺(2 mol/L的THF溶液, 20 mL, 40 mmol)的EtOAc(20 mL)溶液與室溫攪拌1.25小時。體系加入三乙醯氧基硼氫化鈉(9.85g, 46.28 mmol)，室溫攪拌24小時。體系過濾，濾液減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM：MeOH=10:1，v/v洗脫)，得到中間體B1-02 (2.21 g)。MS: m/z 158 [M+1]+ 。Step a: A solution of intermediate B1-01 (2.11 g, 16.47 mmol) and dimethylamine (2 mol/L in THF, 20 mL, 40 mmol) in EtOAc (20 mL) was stirred at room temperature for 1.25 hours. Sodium triacetoxyborohydride (9.85 g, 46.28 mmol) was added to the system, and the mixture was stirred at room temperature for 24 hours. The system was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=10:1, v/v) to give Intermediate B1-02 (2.21 g). MS: m/z 158 [M+1] + .

步驟b：於0℃，向中間體B1-02 (2.01 g, 12.79mmol)的THF(10mL)溶液中加入氫化鋁鋰(1.01 g, 14.85 mmol)，室溫攪拌1.5小時。反應體系以水(20 mL)淬滅，過濾。加碳酸鉀固體至濾液飽和，以EtOAc (3×20 mL)萃取，有機相以無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM：MeOH=20:1，v/v洗脫)，得到中間體B1 (653 mg)。 MS: m/z 130 [M+1]+ 。Step b: Lithium aluminum hydride (1.01 g, 14.85 mmol) was added to a solution of intermediate B1-02 (2.01 g, 12.79 mmol) in THF (10 mL) at 0°C, and the mixture was stirred at room temperature for 1.5 hours. The reaction system was quenched with water (20 mL) and filtered. Solid potassium carbonate was added until the filtrate was saturated, extracted with EtOAc (3 x 20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=20:1, v/v) to give Intermediate B1 (653 mg). MS: m/z 130 [M+1] + .

使用上述工藝或修改工藝，以相應的原料合成了以下中間體。

Figure 02_image1263
Figure 02_image1265
Figure 02_image1267
Figure 02_image1269
Figure 02_image1271
Figure 02_image1273
Figure 02_image1275
    Using the above procedure or a modified procedure, the following intermediates were synthesized from the corresponding starting materials.
Figure 02_image1263
Figure 02_image1265
Figure 02_image1267
Figure 02_image1269
Figure 02_image1271
Figure 02_image1273
Figure 02_image1275

中間體B2

Figure 02_image1277
Intermediate B2
Figure 02_image1277

步驟a：中間體B2-01 (1.29 g, 8.98 mmol)、福馬林(3.7 mL)和甲酸(6 mL)的溶液置於50mL封管中於110℃攪拌19小時。體系降至室溫，加入濃鹽酸(3 mL)，減壓濃縮。殘餘物以異丙醇(5 mL)和乙醚(10 mL)分散，體系置於冰箱靜置1.5小時。上層清液棄去，底層殘餘物以正己烷(2×5 mL)洗滌。殘餘物真空乾燥得到中間體B2-02 (1328 mg)。MS: m/z 172 [M+1]+ 。Step a: A solution of intermediate B2-01 (1.29 g, 8.98 mmol), formalin (3.7 mL) and formic acid (6 mL) was placed in a 50 mL sealed tube and stirred at 110 °C for 19 hours. The system was cooled to room temperature, concentrated hydrochloric acid (3 mL) was added, and the mixture was concentrated under reduced pressure. The residue was dispersed with isopropanol (5 mL) and ether (10 mL), and the system was placed in a refrigerator to stand for 1.5 hours. The supernatant was discarded and the bottom residue was washed with n-hexane (2 x 5 mL). The residue was dried in vacuo to give Intermediate B2-02 (1328 mg). MS: m/z 172 [M+1] + .

步驟b：將中間體B2-02 (1.18 g, 5.68)加入到氫化鋁鋰(1mol/L的THF溶液, 31mL, 31mmol)中，室溫攪拌反應2.5小時。體系以水(1.2 mL)、氫氧化鈉溶液(4 mol/L, 1.2 mL)和水(3.6 mL)淬滅，過濾。濾液濃縮。殘餘物以矽膠柱層析法純化(以DCM：MeOH=4:1，v/v洗脫)，得到中間體B2 (180 mg)。MS: m/z 158 [M+1]+ 。Step b: Intermediate B2-02 (1.18 g, 5.68) was added to lithium aluminum hydride (1 mol/L THF solution, 31 mL, 31 mmol), and the reaction was stirred at room temperature for 2.5 hours. The system was quenched with water (1.2 mL), sodium hydroxide solution (4 mol/L, 1.2 mL) and water (3.6 mL) and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=4:1, v/v) to give Intermediate B2 (180 mg). MS: m/z 158 [M+1] + .

中間體B3

Figure 02_image1278
Intermediate B3
Figure 02_image1278

步驟a：將中間體B3-01 (1.00 g, 4.36 mmol)和甲酸(6 mL)溶液置於48mL封管中75℃攪拌1.5小時。加入福馬林(5 mL)，110℃攪拌反應4小時。體系降至室溫，加入濃鹽酸(5mL)，體系減壓濃縮。殘餘物以異丙醇(5 mL)和乙醚(10 mL)分散，體系置於冰箱靜置1.5小時。上層清液棄去，底層殘餘物以正己烷(2×5 mL)洗滌。殘餘物真空乾燥得到中間體B3-02 (760 mg)。MS: m/z 158 [M+1]+ 。Step a: A solution of intermediate B3-01 (1.00 g, 4.36 mmol) and formic acid (6 mL) was placed in a 48 mL sealed tube and stirred at 75°C for 1.5 hours. Formalin (5 mL) was added, and the reaction was stirred at 110° C. for 4 hours. The system was cooled to room temperature, concentrated hydrochloric acid (5 mL) was added, and the system was concentrated under reduced pressure. The residue was dispersed with isopropanol (5 mL) and ether (10 mL), and the system was placed in a refrigerator to stand for 1.5 hours. The supernatant was discarded and the bottom residue was washed with n-hexane (2 x 5 mL). The residue was dried in vacuo to give Intermediate B3-02 (760 mg). MS: m/z 158 [M+1] + .

步驟b：向0℃的中間體B3-02 (760 mg, 3.92 mmol)的THF(10 mL)溶液中加入氫化鋁鋰(364 mg, 9.59 mmol)，室溫攪拌3小時。反應體系以冰水(0.8 mL)淬滅，過濾。濾液減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM：MeOH=100:1 ~ 10:1，v/v洗脫)，得到中間體B3 (358 mg)。MS: m/z 144 [M+1]+ 。Step b: To a solution of Intermediate B3-02 (760 mg, 3.92 mmol) in THF (10 mL) at 0°C was added lithium aluminum hydride (364 mg, 9.59 mmol) and stirred at room temperature for 3 hours. The reaction system was quenched with ice water (0.8 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=100:1~10:1, v/v) to give Intermediate B3 (358 mg). MS: m/z 144 [M+1] + .

使用上述工藝或修改工藝，以相應的原料合成了以下中間體。

Figure 02_image1279
Figure 02_image1281
 Using the above procedure or a modified procedure, the following intermediates were synthesized from the corresponding starting materials.
Figure 02_image1279
Figure 02_image1281

中間體B4

Figure 02_image1283
Intermediate B4
Figure 02_image1283

步驟a：將中間體B4-01 (300 mg, 2.97 mmol)、1,4-二溴丁烷(672 mg,3.11 mmol)和K2 CO3 (1.07 g, 7.75 mmol)的乙腈(15 mL)溶液在室溫下攪拌15小時。將反應體系過濾，濾液減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM：MeOH= 10:1，v/v洗脫)，得到中間體B4 (183 mg). MS: m/z 156 [M+1]+ 。Step a: Intermediate B4-01 (300 mg, 2.97 mmol) , 1,4- dibromobutane (672 mg, 3.11 mmol) in acetonitrile and K 2 CO 3 (1.07 g, 7.75 mmol) in (15 mL) The solution was stirred at room temperature for 15 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=10:1, v/v) to give Intermediate B4 (183 mg). MS: m/z 156 [M+1] + .

使用上述工藝或修改工藝，以相應的原料合成了以下中間體。

Figure 02_image1284
Using the above procedure or a modified procedure, the following intermediates were synthesized from the corresponding starting materials.
Figure 02_image1284

中間體B5

Figure 02_image1286
Intermediate B5
Figure 02_image1286

步驟a：將中間體B5-01 (192 mg, 1.40 mmol)和福馬林(0.6 mL)的甲酸(1 mL)置於50 mL封管中在110℃攪拌19小時。冷卻至室溫，加入濃鹽酸(0.5 mL)和甲酸(5 mL)，體系減壓濃縮。殘餘物以甲醇(10mL)和碳酸氫鈉(3.12 g)分散，然後過濾。濾液減壓濃縮，並以矽膠柱層析法純化(以DCM：MeOH=4:1，v/v洗脫)，得到中間體B5 (161 mg). MS: m/z 130 [M+1]+ 。Step a: Intermediate B5-01 (192 mg, 1.40 mmol) and formalin (0.6 mL) in formic acid (1 mL) were placed in a 50 mL sealed tube and stirred at 110°C for 19 hours. After cooling to room temperature, concentrated hydrochloric acid (0.5 mL) and formic acid (5 mL) were added, and the system was concentrated under reduced pressure. The residue was dispersed with methanol (10 mL) and sodium bicarbonate (3.12 g), then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with DCM:MeOH=4:1, v/v) to give Intermediate B5 (161 mg). MS: m/z 130 [M+1] + .

使用上述工藝或修改工藝，以相應的原料合成了以下中間體。

Figure 02_image1287
Using the above procedure or a modified procedure, the following intermediates were synthesized from the corresponding starting materials.
Figure 02_image1287

中間體B6

Figure 02_image1289
根據WO2009093012 A1的步驟，以1,1-環丙基二甲酸單甲酯為原料經三步合成中間體B6。Intermediate B6
Figure 02_image1289
According to the procedure of WO2009093012 A1, the intermediate B6 was synthesized in three steps with 1,1-cyclopropyldicarboxylate monomethyl ester as the raw material.

中間體B7

Figure 02_image1290
Intermediate B7
Figure 02_image1290

步驟a：向中間體B6-01 (6.34 g, 43.99 mmol)的DCM(50 mL)溶液中滴加DIEA (3 滴)和草醯氯(7.71 g, 60.74 mmol)。體系於室溫下攪拌反應1.5小時，然後減壓濃縮。將殘餘物滴加到N-甲基哌嗪(5.86 g, 58.51 mmol)和三乙胺(9.30 g, 91.91 mmol)的DCM(100mL)溶液中。體系攪拌反應1.5小時，加水(50 mL)淬滅。收集有機相，無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM：MeOH= 100/1-30/1，v/v洗脫)，得到中間體B7-01 (9.61 g). MS: m/z 227 [M+1]+ 。Step a: To a solution of Intermediate B6-01 (6.34 g, 43.99 mmol) in DCM (50 mL) was added DIEA (3 drops) and oxalyl chloride (7.71 g, 60.74 mmol) dropwise. The system was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. The residue was added dropwise to a solution of N-methylpiperazine (5.86 g, 58.51 mmol) and triethylamine (9.30 g, 91.91 mmol) in DCM (100 mL). The system was stirred for 1.5 hours and quenched by adding water (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=100/1-30/1, v/v) to give Intermediate B7-01 (9.61 g). MS: m/z 227 [M+ 1] + .

步驟b：向中間體B7-01 (2.94 g, 12.99 mmol)的甲醇(30 mL)溶液中加入CaCl2 (1.73 g)和NaBH4 (2.96 g, 78.24 mmol)。反應3小時後再次加入NaBH4 (1.04 g)。體系繼續攪拌反應20小時後，以水(5 mL)淬滅並過濾。收集濾液並減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM：MeOH= 50/1-10/1，v/v洗脫)，得到中間體B7 (0.99 g). MS: m/z 199 [M+1]+ 。Step b: (30 mL) was added CaCl 2 (1.73 g) and NaBH 4 (2.96 g, 78.24 mmol ) of Intermediate B7-01 (2.94 g, 12.99 mmol) in methanol. After 3 hours the reaction was again added NaBH 4 (1.04 g). After the system continued to stir for 20 hours, it was quenched with water (5 mL) and filtered. The filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=50/1-10/1, v/v) to give Intermediate B7 (0.99 g). MS: m/z 199 [M+1] + .

使用上述工藝或修改工藝(中間體B6/中間體B7)，以相應的原料合成了以下中間體。

Figure 02_image1291
Figure 02_image1293
Figure 02_image1295
Figure 02_image1297
Figure 02_image1299
Figure 02_image1301
Figure 02_image1303
Figure 02_image1305
Figure 02_image1307
Figure 02_image1309
Figure 02_image1311
    Using the above procedure or a modified procedure (Intermediate B6/Intermediate B7), the following intermediates were synthesized from the corresponding starting materials.
Figure 02_image1291
Figure 02_image1293
Figure 02_image1295
Figure 02_image1297
Figure 02_image1299
Figure 02_image1301
Figure 02_image1303
Figure 02_image1305
Figure 02_image1307
Figure 02_image1309
Figure 02_image1311

中間體B8

Figure 02_image1313
Intermediate B8
Figure 02_image1313

步驟a：向25℃-30℃的中間體B8-01 (5.18 g, 38.60 mmol)和二聚醋酸銠(78 mg, 0.18mmol)的乙醚(15 mL)溶液中，滴加重氮乙酸乙酯(4.78g, 41.89 mmol)。體系攪拌反應22小時後過濾。濾液減壓濃縮並以矽膠柱層析法純化(以EtOAc：Hex =1:25，v/v洗脫)，得到中間體B8-02 (2060 mg)。Step a: To a solution of intermediate B8-01 (5.18 g, 38.60 mmol) and rhodium dimerized acetate (78 mg, 0.18 mmol) in ether (15 mL) at 25°C-30°C, add dropwise ethyl diazoacetate ( 4.78 g, 41.89 mmol). The system was stirred and reacted for 22 hours and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with EtOAc:Hex = 1:25, v/v) to give Intermediate B8-02 (2060 mg).

步驟b:將中間體B8-02 (2286 mg, 9.76 mmol)和NaOH (3.22g, 80.50 mmol)的乙醇(25 mL)和水(25 mL)溶液在70℃攪拌反應2小時。反應體系以濃鹽酸調pH=7並減壓濃縮。殘餘物乙酸乙酯和檸檬酸水溶液分散。收集有機相，並以飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物以矽膠柱層析法純化(以Hex ：EtOAc =4:1，v/v洗脫)，得到B8-03 (1196 mg). MS: m/z 191 [M-1]+ 。Step b: A solution of Intermediate B8-02 (2286 mg, 9.76 mmol) and NaOH (3.22 g, 80.50 mmol) in ethanol (25 mL) and water (25 mL) was stirred at 70 °C for 2 hours. The reaction system was adjusted to pH=7 with concentrated hydrochloric acid and concentrated under reduced pressure. The residue was dispersed in ethyl acetate and aqueous citric acid. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with Hex:EtOAc = 4:1, v/v) to give B8-03 (1196 mg). MS: m/z 191 [M-1] + .

步驟c：向中間體B8-03 (645 mg, 3.13 mmol)、HATU (1310 mg, 3.45 mmol)和二甲胺鹽酸鹽(445 mg, 5.46 mmol)的DCM(50 mL)溶液中滴加DIEA (1243 mg, 9.62 mmol)，體系室溫攪拌2小時。體系減壓濃縮並以矽膠柱層析法純化(以MeOH : DCM = 1 : 40，v/v洗脫)，得到中間體B8-04 (685 mg). MS: m/z 220 [M+1]+ 。Step c: To a solution of Intermediate B8-03 (645 mg, 3.13 mmol), HATU (1310 mg, 3.45 mmol) and dimethylamine hydrochloride (445 mg, 5.46 mmol) in DCM (50 mL) was added dropwise DIEA (1243 mg, 9.62 mmol), and the system was stirred at room temperature for 2 hours. The system was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with MeOH : DCM = 1 : 40, v/v) to give Intermediate B8-04 (685 mg). MS: m/z 220 [M+1 ] + .

步驟d：將中間體B8-04 (760 mg, 3.92 mmol)加入到氫化鋁鋰(12 mL, 1 mol/L的THF溶液)的THF (8 mL)溶液中，於40℃攪拌2小時。反應體系以冰水淬滅並過濾。濾液減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM : MeOH = 8:1，v/v洗脫)，得到中間體B8-05 (576 mg). MS: m/z 206 [M+1]+ 。Step d: Intermediate B8-04 (760 mg, 3.92 mmol) was added to a solution of lithium aluminum hydride (12 mL, 1 mol/L in THF) in THF (8 mL) and stirred at 40°C for 2 hours. The reaction system was quenched with ice water and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH = 8:1, v/v) to give Intermediate B8-05 (576 mg). MS: m/z 206 [M+1] + .

步驟e：將鈀碳(10%, 0.53 g)加入到中間體B8-05 (264 mg, 1.20 mmol)的MeOH (25 mL)溶液中。體系以氫氣置換三次，於45℃攪拌反應2.5小時。反應體系過濾。濾液減壓濃縮得到中間體B8 (153 mg). MS: m/z 116 [M+1]+ 。Step e: Palladium on carbon (10%, 0.53 g) was added to a solution of Intermediate B8-05 (264 mg, 1.20 mmol) in MeOH (25 mL). The system was replaced with hydrogen three times, and the reaction was stirred at 45°C for 2.5 hours. The reaction system was filtered. The filtrate was concentrated under reduced pressure to give Intermediate B8 (153 mg). MS: m/z 116 [M+1] + .

中間體B9

Figure 02_image1314
Intermediate B9
Figure 02_image1314

步驟a：向中間體B6-01 (7.61 g, 52.80 mmol)的DCM(50 mL)溶液中滴加DIEA (3 滴)和草醯氯(8.89 g,70.04 mmol)。體系於25℃攪拌反應2小時後減壓濃縮。殘餘物滴加到1 -第三丁氧羰基哌嗪(12.60 g, 67.65 mmol)和三乙胺(10.66 g, 105.35 mmol)的DCM(70 mL)溶液中。體系攪拌反應0.5小時後以水(50 mL)淬滅。收集有機相，以無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM : MeOH = 50:1，v/v洗脫)，得到中間體B9-01 (16.69 g). MS: m/z 313 [M+1]+ 。Step a: To a solution of Intermediate B6-01 (7.61 g, 52.80 mmol) in DCM (50 mL) was added DIEA (3 drops) and oxalyl chloride (8.89 g, 70.04 mmol) dropwise. The system was stirred at 25°C for 2 hours and then concentrated under reduced pressure. The residue was added dropwise to a solution of 1-tert-butoxycarbonylpiperazine (12.60 g, 67.65 mmol) and triethylamine (10.66 g, 105.35 mmol) in DCM (70 mL). The system was stirred for 0.5 hours and then quenched with water (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH = 50:1, v/v) to give Intermediate B9-01 (16.69 g). MS: m/z 313 [M+1] + .

步驟b：向中間體B9-01 (16.69 g, 53.43 mmol)的EtOAc (30 mL)溶液中加入HCl (4 mol/L 的乙酸乙酯溶液, 85 mL)。體系攪拌反應3小時後減壓濃縮。殘餘物以EtOAc (100 mL)分散。體系以三乙胺調pH=12，過濾。濾液減壓濃縮得到中間體B9-02 (12.02 g). MS: m/z 213 [M+1]+ 。Step b: To a solution of Intermediate B9-01 (16.69 g, 53.43 mmol) in EtOAc (30 mL) was added HCl (4 mol/L in ethyl acetate, 85 mL). The system was stirred for 3 hours and then concentrated under reduced pressure. The residue was dispersed with EtOAc (100 mL). The system was adjusted to pH=12 with triethylamine, and filtered. The filtrate was concentrated under reduced pressure to give Intermediate B9-02 (12.02 g). MS: m/z 213 [M+1] + .

步驟c：控溫-20℃以下，向中間體B9-02 (12.02 g, 56.63 mmol)的THF (150 mL)溶液中，分批投入氫化鋁鋰(4.34 g, 114.36 mmol)。體系反應3小時後，再次分批投入氫化鋁鋰(1.05 g)。體系繼續攪拌反應3小時後，以水(5 mL)、氫氧化鈉溶液(15%, 5 mL)和水(15 mL)淬滅，過濾。收集濾液並減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM : MeOH =10/1-3/1，v/v洗脫)，得到中間體B9-03 (2.39 g). MS: m/z 171 [M+1]+ 。Step c: Control the temperature below -20 °C, and add lithium aluminum hydride (4.34 g, 114.36 mmol) into a solution of intermediate B9-02 (12.02 g, 56.63 mmol) in THF (150 mL) in batches. After the system was reacted for 3 hours, lithium aluminum hydride (1.05 g) was added in batches again. After the system continued to stir for 3 hours, it was quenched with water (5 mL), sodium hydroxide solution (15%, 5 mL) and water (15 mL), and filtered. The filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=10/1-3/1, v/v) to give Intermediate B9-03 (2.39 g). MS: m/z 171 [M+ 1] + .

步驟d：控溫-70℃以下，向中間體B9-03 (1.42 g, 8.34 mmol)的DCM(15 mL)溶液中，滴加乙醯氯(447 mg, 5.69 mmol)的DCM (1 mL)溶液。體系攪拌反應20分鐘。體系以三乙胺調pH=12。體系過濾，濾液減壓濃縮。殘餘物分散於EtOAc(15 mL)中，過濾。收集濾液並減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM : MeOH =50/1，v/v洗脫)，得到中間體B9 (1.13 g). MS: m/z 227 [M+1]+ 。Step d: To a solution of intermediate B9-03 (1.42 g, 8.34 mmol) in DCM (15 mL) was added dropwise acetonitrile chloride (447 mg, 5.69 mmol) in DCM (1 mL) at a temperature below -70 °C solution. The system was stirred and reacted for 20 minutes. The pH of the system was adjusted to 12 with triethylamine. The system was filtered, and the filtrate was concentrated under reduced pressure. The residue was dispersed in EtOAc (15 mL) and filtered. The filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=50/1, v/v) to give Intermediate B9 (1.13 g). MS: m/z 227 [M+1] + .

中間體B10

Figure 02_image1315
Intermediate B10
Figure 02_image1315

步驟a：將戴斯-馬丁氧化劑(7.40 g, 17.45 mmol)分批加入到中間體B10-01 (1.50 g, 11.61 mmol)的DCM(30mL)溶液中。體系攪拌反應17小時後，加入DCM(100 mL)和碳酸鉀溶液(40%, 20 mL)。體系過濾，濾液分液。有機相減壓濃縮。所得殘餘物以矽膠柱層析法純化(以DCM : MeOH =20/1，v/v洗脫)，得到中間體B10-02 (0.64 g). MS: m/z 128 [M+1]+ 。Step a: Dess-Martin Oxidant (7.40 g, 17.45 mmol) was added portionwise to a solution of Intermediate B10-01 (1.50 g, 11.61 mmol) in DCM (30 mL). After the system was stirred for 17 hours, DCM (100 mL) and potassium carbonate solution (40%, 20 mL) were added. The system was filtered, and the filtrate was separated. The organic phase was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with DCM:MeOH=20/1, v/v) to give Intermediate B10-02 (0.64 g). MS: m/z 128 [M+1] + .

步驟b：控溫-50℃以下，向中間體B10-02 (0.64 g, 5.03 mmol)的THF(10 mL)溶液中，滴加甲基鋰(1 mol/L的THF溶液, 5 mL)。攪拌反應19小時後，體系減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM : MeOH =20：1，v/v洗脫)，得到中間體B10 (408 mg). MS: m/z 144 [M+1]+ 。Step b: Controlling the temperature below -50°C, to a solution of intermediate B10-02 (0.64 g, 5.03 mmol) in THF (10 mL) was added dropwise methyllithium (1 mol/L in THF, 5 mL). After stirring the reaction for 19 hours, the system was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH=20:1, v/v) to give Intermediate B10 (408 mg). MS: m/z 144 [M+1] + .

中間體C1

Figure 02_image1316
根據Journal of Organic Chemistry (2016), 81(22), 10791-10801 的步驟，以1,8-二溴萘為起始原料一步合成中間體C1。Intermediate C1
Figure 02_image1316
According to the steps of Journal of Organic Chemistry (2016), 81(22), 10791-10801 , intermediate C1 was synthesized in one step using 1,8-dibromonaphthalene as the starting material.

中間體C2

Figure 02_image1317
根據US20180072723 A1的步驟，以1,8-二氨基萘為起始原料經3步合成中間體C2。Intermediate C2
Figure 02_image1317
According to the steps of US20180072723 A1, 1,8-diaminonaphthalene was used as the starting material to synthesize intermediate C2 in 3 steps.

中間體D1

Figure 02_image1318
Intermediate D1
Figure 02_image1318

步驟a：向中間體A2 (3.14 g, 7.76 mmol)、中間體C1 ( 2.11 g, 9.54 mmol)和Cs2 CO3 (7.72 g, 23.69 mmol)的甲苯(50 mL)溶液中加入RuPhos (316 mg, 0.70 mmol) 和 Pd2 (dba)3 (307 mg, 0.34 mmol)，氮氣置換三次。體系於100℃攪拌反應24小時。反應結束後，體系過濾。濾液減壓濃縮。殘餘物以矽膠柱層析法純化(以Hex: EtOAc = 10 : 1，v/v洗脫)，得到棕色固體中間體D1-01 (2.42 g)。MS: m/z 545 [M+H]+ 。Step a: Intermediate A2 (3.14 g, 7.76 mmol) , Intermediate C1 (2.11 g, 9.54 mmol) and Cs 2 CO 3 (7.72 g, 23.69 mmol) in toluene (50 mL) was added RuPhos (316 mg , 0.70 mmol) and Pd 2 (dba) 3 (307 mg, 0.34 mmol), replaced with nitrogen three times. The system was stirred at 100°C for 24 hours. After the reaction was completed, the system was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with Hex:EtOAc = 10:1, v/v) to give intermediate D1-01 (2.42 g) as a brown solid. MS: m/z 545 [M+H] + .

步驟b:向0℃的中間體D1-01 (2.42 g, 4.44 mmol)的DCM(5 mL)溶液中加入m-CPBA (965mg, 4.75 mmol, 85%)，體系於0℃反應45分鐘。加入DCM (30 mL)，再以飽和Na2 S2 O3 (20 mL)淬滅，體系分液。收集有機相，以飽和NaHCO3 (20 mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM: MeOH = 80:1-20:1，v/v洗脫)，得到黃色固體中間體D1-02 (2.19 g)。MS: m/z 561 [M+H]+ 。Step b: m-CPBA (965 mg, 4.75 mmol, 85%) was added to a solution of intermediate D1-01 (2.42 g, 4.44 mmol) in DCM (5 mL) at 0 °C, and the system was reacted at 0 °C for 45 minutes. Was added DCM (30 mL), then saturated Na 2 S 2 O 3 (20 mL) quenched liquid separation system. Collect the organic phase with saturated NaHCO 3 (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH = 80:1-20:1, v/v) to give intermediate D1-02 (2.19 g) as a yellow solid. MS: m/z 561 [M+H] + .

步驟c：氮氣保護下，向-20℃的中間體B4 (507 mg, 3.27 mmol)的乾燥THF(6 mL)溶液中加入t-BuONa (626 mg, 6.54 mmol)，攪拌反應30分鐘。然後將中間體D1-02 (610 mg, 1.09mmol)的乾燥THF(4 mL)溶液滴加到反應體系中，控溫-20℃，攪拌反應20分鐘。反應結束後，體系以水(20 mL)淬滅，以EtOAc (20 mL*2)萃取。合併有機相，減壓濃縮。殘餘物以矽膠柱層析法純化(以DCM: MeOH = 30:1，v/v洗脫)，得到紅色油狀物中間體D1 (597 mg)。MS: m/z 652 [M+H]+ 。Step c: To a solution of Intermediate B4 (507 mg, 3.27 mmol) in dry THF (6 mL) at -20°C was added t-BuONa (626 mg, 6.54 mmol) under nitrogen protection, and the reaction was stirred for 30 minutes. Then, a solution of intermediate D1-02 (610 mg, 1.09 mmol) in dry THF (4 mL) was added dropwise to the reaction system, the temperature was controlled to -20°C, and the reaction was stirred for 20 minutes. After the reaction was completed, the system was quenched with water (20 mL) and extracted with EtOAc (20 mL*2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH = 30:1, v/v) to give Intermediate D1 (597 mg) as a red oil. MS: m/z 652 [M+H] + .

使用上述工藝或修改工藝，以相應的原料合成了以下中間體：

Figure 02_image1319
Figure 02_image1321
Figure 02_image1323
Figure 02_image1325
Figure 02_image1327
Figure 02_image1329
Figure 02_image1331
Figure 02_image1333
Figure 02_image1335
Figure 02_image1337
Figure 02_image1339
Figure 02_image1341
Figure 02_image1343
Figure 02_image1345
       Using the above process or modified process, the following intermediates were synthesized from the corresponding starting materials:
Figure 02_image1319
Figure 02_image1321
Figure 02_image1323
Figure 02_image1325
Figure 02_image1327
Figure 02_image1329
Figure 02_image1331
Figure 02_image1333
Figure 02_image1335
Figure 02_image1337
Figure 02_image1339
Figure 02_image1341
Figure 02_image1343
Figure 02_image1345

中間體E1

Figure 02_image1347
根據WO2019099524的步驟，以4-溴丁烯酸乙酯為起始原料經2步合成中間體E1。Intermediate E1
Figure 02_image1347
According to the procedure of WO2019099524, the intermediate E1 was synthesized in 2 steps using ethyl 4-bromobutenoate as the starting material.

中間體E2

Figure 02_image1348
根據WO2013010869 A1的步驟，以(E)-4-溴丁-2-烯酸為起始原料經一步合成中間體E2。Intermediate E2
Figure 02_image1348
According to the procedure of WO2013010869 A1, (E)-4-bromobut-2-enoic acid was used as the starting material to synthesize intermediate E2 in one step.

中間體E3

Figure 02_image1349
根據WO2019099524的步驟，以(E)-4-溴丁-2-烯酸為起始原料經一步合成中間體E3。Intermediate E3
Figure 02_image1349
According to the procedure of WO2019099524, intermediate E3 was synthesized in one step using (E)-4-bromobut-2-enoic acid as the starting material.

實施例1

Figure 02_image1350
Example 1
Figure 02_image1350

步驟a：向中間體A1 (300 mg, 0.62 mmol)、反式-4-(二甲基氨基)環己醇(140 mg, 0.98 mmol)和第三丁醇鈉(170 mg,1.77 mmol)的甲苯(10 mL)溶液中，加入BINAP (65 mg,0.10 mmol) 和 Pd2 (dba)3 (55 mg,0.06 mmol)，氮氣置換三次， 95℃攪拌反應2.5小時。體系以乙酸乙酯(30 mL) 和水 (40 mL)稀釋，收集有機相。有機相以40 mL飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物以製備薄層色譜法純化(DCM: MeOH = 9: 1，v/v)，得到化合物1-1 (239 mg, 0.41 mmol)。MS: m/z 590 [M+1]+ 。Step a: To intermediate A1 (300 mg, 0.62 mmol), trans-4-(dimethylamino)cyclohexanol (140 mg, 0.98 mmol) and sodium tert-butoxide (170 mg, 1.77 mmol) To the toluene (10 mL) solution, BINAP (65 mg, 0.10 mmol) and Pd 2 (dba) 3 (55 mg, 0.06 mmol) were added, nitrogen was replaced three times, and the reaction was stirred at 95° C. for 2.5 hours. The system was diluted with ethyl acetate (30 mL) and water (40 mL), and the organic phase was collected. The organic phase was washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM:MeOH=9:1, v/v) to give compound 1-1 (239 mg, 0.41 mmol). MS: m/z 590 [M+1] + .

步驟b：將鈀碳(375 mg, 10%)加入到化合物1-1 (229 mg, 0.39 mmol)的甲醇(10 mL)溶液中。體系以氫氣置換三次。體系於氫氣氛圍下，在60℃攪拌1小時。體系過濾，濾餅以20 mL甲醇淋洗。濾液減壓濃縮得到化合物1-2 (193 mg, 0.39 mmol)。MS: m/z 500 [M+1]+ 。Step b: Palladium on carbon (375 mg, 10%) was added to a solution of compound 1-1 (229 mg, 0.39 mmol) in methanol (10 mL). The system was replaced three times with hydrogen. The system was stirred at 60°C for 1 hour under a hydrogen atmosphere. The system was filtered, and the filter cake was rinsed with 20 mL of methanol. The filtrate was concentrated under reduced pressure to obtain compound 1-2 (193 mg, 0.39 mmol). MS: m/z 500 [M+1] + .

步驟c：向化合物1-2 (193 mg,0.39 mmol)、1-溴化萘(140 mg,0.68 mmol)和Cs2 CO3 (315 mg,0.97 mmol)的甲苯(10 mL)溶液中加入RuPhos (53 mg,0.11 mmol) 和Pd2 (dba)3 (37 mg,0.04 mmol)，氮氣置換三次，100℃攪拌6小時。體系過濾並減壓濃縮。殘餘物以製備薄層色譜法純化(DCM: MeOH = 9: 1，v/v)，得到化合物1-3 (141 mg, 0.23 mmol)。MS: m/z 626 [M+1]+ 。Step c: 1-2 (193 mg, 0.39 mmol) of the compound, 1-naphthyl bromide (140 mg, 0.68 mmol) and Cs 2 CO 3 (315 mg, 0.97 mmol) in toluene (10 mL) was added a solution of RuPhos (53 mg, 0.11 mmol) and Pd 2 (dba) 3 (37 mg, 0.04 mmol), replaced with nitrogen three times, and stirred at 100° C. for 6 hours. The system was filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM:MeOH=9:1, v/v) to give compound 1-3 (141 mg, 0.23 mmol). MS: m/z 626 [M+1] + .

步驟d：向化合物1-3 (141 mg, 0.23mmol)的DCM(3 mL)溶液中加入TFA (1.2mL)。反應混合物於25℃攪拌0.5小時。反應結束，體系減壓濃縮。殘餘物溶於DCM(5 mL)。將三乙胺 (0.5 mL)和丙烯醯氯 (69 mg, 0.76 mmol)加入到溶液中，體系與25℃反應10分鐘。體系以DCM (40 mL) 和水 (30 mL)稀釋，收集有機相。有機相以30 mL飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物以製備薄層色譜法純化(DCM: MeOH = 9: 1，v/v)，得到化合物1 (68 mg)。 MS: m/z 580 [M+1]+ 。1 H NMR (400 MHz,MeOH-d4 ) δ 8.31 – 8.18 (m, 1H), 7.93 – 7.82 (m, 1H), 7.62 (d, 1H), 7.57 – 7.48 (m, 2H), 7.44 (t, 1H), 7.21 (d, 1H), 6.84 (s, 1H), 6.31 (d, 1H), 5.86 (d, 1H), 5.16 – 4.96 (m, 2H), 4.33 – 4.03 (m, 4H), 3.65 (s, 1H), 3.44 (s, 2H), 3.40 – 3.21 (m, 3H), 3.13 – 2.95 (m, 3H), 2.88 (s, 6H), 2.38 (s, 2H), 2.18 (d, 2H), 1.80 (d, 2H), 1.72 – 1.53 (m, 2H), 1.43 – 1.22 (m, 2H)。Step d: To a solution of compound 1-3 (141 mg, 0.23 mmol) in DCM (3 mL) was added TFA (1.2 mL). The reaction mixture was stirred at 25°C for 0.5 hours. After the reaction was completed, the system was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL). Triethylamine (0.5 mL) and acryl chloride (69 mg, 0.76 mmol) were added to the solution, and the system was reacted with 25° C. for 10 minutes. The system was diluted with DCM (40 mL) and water (30 mL) and the organic phase was collected. The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM:MeOH=9:1, v/v) to give compound 1 (68 mg). MS: m/z 580 [M+1] + . 1 H NMR (400 MHz, MeOH-d4 ) δ 8.31 – 8.18 (m, 1H), 7.93 – 7.82 (m, 1H), 7.62 (d, 1H), 7.57 – 7.48 (m, 2H), 7.44 (t, 1H), 7.21 (d, 1H), 6.84 (s, 1H), 6.31 (d, 1H), 5.86 (d, 1H), 5.16 – 4.96 (m, 2H), 4.33 – 4.03 (m, 4H), 3.65 (s, 1H), 3.44 (s, 2H), 3.40 – 3.21 (m, 3H), 3.13 – 2.95 (m, 3H), 2.88 (s, 6H), 2.38 (s, 2H), 2.18 (d, 2H) ), 1.80 (d, 2H), 1.72 – 1.53 (m, 2H), 1.43 – 1.22 (m, 2H).

使用上述工藝或修改工藝，以相應的原料合成了以下化合物。 化合物 化學名稱 結構式 MS: (M+H)+ /1 HNMR 2.          2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(2-甲基-1-氧代-1,2-二氫異喹啉-8-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈

Figure 02_image1351
MS:5971 H NMR (400 MHz, MeOD) δ 7.59 – 7.44 (m, 1H), 7.26 (d, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.72 (s, 1H), 6.50 (d, 1H), 6.19 (d, 1H), 5.73 (d, 1H), 4.97 (s, 1H), 4.54 – 4.37 (m, 1H), 4.36 – 3.86 (m, 5H), 3.61 – 3.38 (m, 4H), 3.19 – 2.81 (m, 8H), 2.81 – 2.58 (m, 6H), 1.35 – 1.02 (m, 3H), 0.86 – 0.55 (m, 4H). 3.          2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1353
 MS:571 4.          2-(1-丙烯醯基-4-(7-(萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1355
 MS:5921 H NMR (400 MHz, CDCl3 ) δ 8.13 (d, 1H), 7.78 (d, 1H), 7.43 (ddd, 4H), 7.08 (d, 1H), 6.51 (s, 1H), 6.32 (d, 1H), 5.75 (d, 1H), 5.01 (s, 1H), 4.33 (dd, 6H), 3.90 (s, 2H), 3.57 (s, 1H), 3.47 – 3.00 (m, 6H), 2.82 (s, 5H), 2.24 (s, 2H), 1.96 (s, 2H), 1.21 (d, 2H), 0.89 (s, 2H), 0.79 (s, 2H). 5.          2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環己基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1357
 MS:6081 H NMR (400 MHz, DMSO) δ 7.76 (d, 1H), 7.70 (d, 1H), 7.46 (dd,1H), 7.35 (dd, 2H), 7.27 (d, 1H), 6.86 (s, 1H), 6.19 (d, 1H),5.78 (d, 1H), 4.01 (dd, 6H), 3.80 – 3.62 (m, 2H), 3.20– 3.04 (m, 5H), 2.86 (s, 4H), 2.64 (s, 7H), 2.19 – 1.97 (m, 3H), 1.92 – 1.67 (m, 3H), 1.23 (dd, 26.6 Hz, 6H) 6.          2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環己基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1359
 MS:6121 H NMR (400 MHz, DMSO) δ 7.80 – 7.60 (m, 3H), 7.40 (t, 1H), 6.86 (s, 1H), 6.19 (d, 1H), 5.78 (d, 1H), 4.88 (d, 1H), 4.08 (dd, 3H), 4.02 (s, 4H), 3.06 (ddd, 7H), 2.78 (s, 2H), 2.66 (s, 6H), 2.16 (d, 1H), 2.04 (s,1H), 1.86 (d, 2H), 1.73 (d, 1H), 1.41 – 1.16 (m, 4H), 0.99 (d, 1H). 7.          2-(1-丙烯醯基-4-(2-(3-(二甲基氨基)環丁氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1361
 MS:552 8.          2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環丁基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1363
 MS:5661 H NMR (400 MHz, MeOD) δ 8.21 – 8.02 (m, 1H), 7.84 – 7.66 (m, 1H), 7.52 (d, 1H), 7.46 – 7.24 (m, 3H), 7.11 (d, 1H), 6.74 (s, 1H), 6.19 (d, 1H), 5.74 (d, 1H), 4.99 (s, 1H), 4.56 – 4.37 (m, 1H), 4.38 – 3.90 (m, 5H), 3.69 – 3.43 (m, 2H), 3.43 – 3.07 (m, 4H), 3.05 – 2.68 (m, 6H), 2.64 – 2.24 (m, 8H), 2.08 – 1.90 (m, 2H). 9.          2-(1-丙烯醯基-4-(2-((1-(二甲基氨基)環丁基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1365
 MS:5661 H NMR (400 MHz, MeOD) δ 8.33 – 8.19 (m, 1H), 7.96 – 7.82 (m, 1H), 7.71 – 7.59 (m, 1H), 7.57 – 7.36 (m, 3H), 7.23 (d, 1H), 6.84 (s, 1H), 6.32 (d, 1H), 5.84 (d, 1H), 5.10 (s, 1H), 4.58 (s, 1H), 4.42 (d, 1H), 4.33 – 4.06 (m, 4H), 3.77 – 3.35 (m, 4H), 3.21 – 2.90 (m, 4H), 2.84 (s, 6H), 2.54 – 2.23 (m, 4H), 2.10 – 1.92 (m, 2H), 1.43 – 1.22 (m, 2H). 10.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環己基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1367
 MS:5781 H NMR (400 MHz, MeOD) δ 8.20 – 8.06 (m, 1H), 7.82 – 7.71 (m, 1H), 7.51 (d, 1H), 7.46 – 7.27 (m, 3H), 7.10 (d, 1H), 6.72 (s, 1H), 6.20 (d, 1H), 5.74 (d, 1H), 4.98 (s, 1H), 4.22 – 3.89 (m, 4H), 3.53 (s, 1H), 3.44 – 3.27 (m, 2H), 3.27 – 2.78 (m, 7H), 2.74 – 2.58 (m, 5H), 2.53 – 2.35 (m, 1H), 2.10 (d, 1H), 2.02 – 1.82 (m, 2H), 1.64 – 1.30 (m, 4H), 1.27 – 1.09 (m, 3H). 11.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環己基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1369
 MS:580 12.     2-(1-丙烯醯基-4-(2-((1-(二甲基氨基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1371
 MS:552 13.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1373
 MS:566 14.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1375
 MS:5801 H NMR (400 MHz, DMSO) δ 8.38 – 8.10 (m, 1H), 8.06 – 7.86 (m, 1H), 7.65 (d, 1H), 7.61–7.40 (m, 3H), 7.23 (d, 1H), 6.88 (s, 1H), 6.20 (d, 1H), 5.79 (d, 1H),4.88 (d, 1H), 4.69 – 4.24 (m, 2H), 4.10 (d, 5H), 3.66 – 3.37 (m, 2H), 3.21 (s, 3H),3.00 (d, 6H), 2.74 (d, 2H), 2.26 (d, 4H), 1.72 (d, 5H), 1.20 (d, 1H). 15.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環己基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1377
 MS:594,1 H NMR (400 MHz, MeOD) δ 8.34 – 8.17 (m, 1H), 7.96 – 7.84 (m, 1H), 7.63 (d, 1H), 7.58 – 7.37 (m, 3H), 7.22 (d, 1H), 6.83 (s, 1H), 6.31 (d, 1H), 5.85 (d, 1H), 5.10 (s, 1H), 4.40 – 4.01 (m, 6H), 3.66 (s, 1H), 3.44 (s, 2H), 3.34 – 3.22 (m, 2H), 3.20 – 2.92 (m, 4H), 2.87 (s, 6H), 2.28 (d, 1H), 2.18 – 1.96 (m, 3H), 1.90 (d, 1H), 1.59 – 1.07 (m, 6H). 16.     2-(1-丙烯醯基-4-(2-((2-(4-甲基哌啶-1-基)環戊基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1379
 MS:621 17.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1381
 MS:5801 H NMR (400 MHz, MeOD) δ 8.24 (d, 1H), 7.87 (d, 1H), 7.61 (d, 1H), 7.56 – 7.47 (m, 2H), 7.44 (t, 1H), 7.21 (d, 1H), 6.82 (s, 1H), 6.30 (d, 1H), 5.85 (d, 1H), 4.38 – 4.07 (m, 7H), 3.77 – 3.57 (m, 1H), 3.52 – 3.40 (m, 1H), 3.12 – 2.83 (m, 4H), 2.72 – 2.57 (m, 1H), 2.52 – 2.40 (m, 1H), 2.31 (s, 6H), 2.23 – 2.10 (m, 1H), 2.05 – 1.82 (m, 2H), 1.81 – 1.67 (m, 1H), 1.66 – 1.40 (m, 3H), 1.39 – 1.17 (m, 2H), 1.05 – 0.95 (m, 1H). 18.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環己基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1383
 MS:5941 H NMR (400 MHz, MeOD) δ 8.21 – 8.06 (m, 1H), 7.85 – 7.69 (m, 1H), 7.52 (d, 1H), 7.46 – 7.24 (m, 3H), 7.10 (d, 1H), 6.72 (s, 1H), 6.20 (d, 1H), 5.74 (d, 1H), 4.99 (s, 1H), 4.57 – 4.40 (m, 2H), 4.22 (d, 1H), 4.16 – 3.90 (m, 3H), 3.53 (s, 1H), 3.33 (s, 2H), 3.27 – 3.05 (m, 2H), 2.87 (d, 5H), 2.75 (s, 6H), 2.16 – 1.75 (m, 4H), 1.68 – 1.28 (m, 6H). 19.     2-(1-丙烯醯基-4-(2-((2-((二甲基氨基)甲基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1385
 MS:566 20.     2-(1-丙烯醯基-4-(2-((1-(二甲基氨基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1387
 MS:5661 H NMR (400 MHz, MeOD) δ 7.67 – 7.48 (m, 2H), 7.39 – 7.26 (m, 1H), 7.26 – 7.08 (m, 3H), 6.70 (s, 1H), 6.19 (d, 1H), 5.00 (s, 1H), 4.47 (s, 1H), 4.33 (s, 2H), 4.21 (d, 1H), 4.14 – 3.89 (m, 3H), 3.69 – 3.49 (m, 1H), 3.48 – 3.27 (m, 2H), 3.18 – 2.90 (m, 4H), 2.86 – 2.75 (m, 4H), 2.63 (d, 1H), 2.38 (d, 6H), 2.32 – 2.19 (m, 1H), 0.90 – 0.54 (m, 4H). 21.     2-(1-丙烯醯基-4-(2-(2-(2-(二甲基氨基)環戊基)乙氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1389
 MS:5941 H NMR (400 MHz, MeOD) δ 8.13 (d, 1H), 7.84 – 7.67 (m, 1H), 7.58 – 7.48 (m, 1H), 7.47 – 7.24 (m, 3H), 7.10 (d, 1H), 6.72 (s, 1H), 6.19 (d, 1H), 5.74 (d, 1H), 4.99 (s, 1H), 4.52 – 4.36 (m, 1H), 4.29 (s, 1H), 4.19 (s, 1H), 4.13 – 3.87 (m, 3H), 3.42 – 3.26 (m, 2H), 3.17 – 2.77 (m, 6H), 2.70 – 2.52 (m, 4H), 2.43 – 2.29 (m, 1H), 2.14 – 1.90 (m, 3H), 1.89 – 1.61 (m, 5H), 1.61 – 1.34 (m, 3H), 0.86 – 0.72 (m, 2H). 22.     2-(1-丙烯醯基-4-(2-(((1R,3S)-3-(二甲基氨基)環戊基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1391
 MS:5941 H NMR (400 MHz, CDCl3 ) δ 7.75 – 7.55 (m, 2H), 7.45 – 7.17 (m, 4H), 6.55 (s, 1H), 6.32 (d, 1H), 5.75 (d, 1H), 4.19 (dd, 4H), 3.36 (d, 3H), 3.11 – 3.00 (m, 5H), 2.84 (s, 3H), 2.72 (s, 7H), 1.32 (dd, 5H), 1.25 (s, 5H), 0.80 (d, 2H) 23.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1393
 MS:5941 H NMR (400 MHz, CDCl3 ) δ 7.70 – 7.52 (m, 2H), 7.31 (ddd,3H), 7.19 – 7.14 (m, 1H), 6.56 (s, 1H), 6.31 (d, 1H), 5.72 (d, 1H), 4.95 (s, 1H), 4.70 (s, 2H), 4.34 –3.91 (m, 4H), 3.80 – 3.57 (m, 2H), 3.43 (s, 2H), 3.23 (s, 2H), 3.10 (s, 2H), 2.85 (s, 5H), 2.74 (d, 5H), 2.56 (d, 1H), 2.23 – 1.88 (m, 4H), 1.72 (s, 2H), 1.29 – 1.13 (m, 2H). 24.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1395
 MS:5941 H NMR (400 MHz, MeOD) δ 7.71 (dd, 4.7 Hz, 2H), 7.48 – 7.41 (m, 1H), 7.38 – 7.32 (m, 2H), 7.31 – 7.23 (m, 1H), 6.91 – 6.73 (m, 1H), 6.31 (d, 1H), 5.85 (d, 1H), 5.15 – 4.93 (m, 1H), 4.68 – 4.37 (m, 4H), 4.25 – 4.04 (m, 2H), 3.95 – 3.80 (m, 2H), 3.72 – 3.47 (m, 4H), 3.28 – 3.17 (m, 2H), 3.11 – 3.03 (m, 1H), 2.93 (d, 3H), 2.90 (s, 6H), 2.79 – 2.68 (m, 1H), 2.66 – 2.49 (m, 1H), 2.46 – 2.35 (m, 1H), 2.27 – 2.15 (m, 1H), 2.06 – 1.50 (m, 5H). 25.     2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((2-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1397
 MS:5981 H NMR (400 MHz, CDCl3 ) δ 7.12 (q, 2H), 6.93 (d, 1H), 6.54 (s, 1H), 6.30 (d, 1H), 5.72 (d, 1H), 4.96 (s, 1H), 4.74 (s, 2H), 4.34 – 3.78 (m, 5H), 3.33 (dd, 5H), 3.11 (s, 1H), 2.86 (d, 7H), 2.71 (s, 2H), 2.13 (s, 3H), 1.94 (s, 1H), 1.74(s, 2H), 1.19 (s, 2H) 26.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(3-氟-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1399
 MS:6161 H NMR (400 MHz, CDCl3 ) δ 7.49 (dd, 1H), 7.07 (d, 1H), 7.02 – 6.90 (m,1H), 6.65 (s, 1H), 6.39 (d, 1H), 5.81 (d, 1H), 5.05 (s, 1H), 4.84 (s, 2H), 4.25 (dd,2H), 4.12 (s, 3H), 3.37 (dd, 5H), 3.18 (s, 1H), 2.94 (d, 7H), 2.80 (s, 2H), 2.18 (dd, 4H), 1.83 (s, 2H), 1.35 – 1.21 (m, 2H) 27.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1401
 MS:5981 H NMR (400 MHz, MeOD) δ 7.70 – 7.52 (m, 2H), 7.52 – 7.43 (m, 1H), 7.35 – 7.20 (m, 1H), 6.71 (s, 1H), 6.19 (d, 1H), 5.80 – 5.66 (m, 1H), 5.00 (s, 1H), 4.44 – 4.30 (m, 1H), 4.25 – 3.97 (m, 3H), 3.90 (s, 2H), 3.53 (s, 1H), 3.16 – 2.99 (m, 3H), 2.91 (s, 2H), 2.77 (s, 2H), 2.59 (d, 3H), 2.40 (s, 6H), 2.02 – 1.41 (m, 7H).    28.     2-(1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(2,3-二甲基氨基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1403
 MS:558 29.     2-(1-丙烯醯基-4-(7-(2-氯-3-氟苯基)-2-((3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1405
 MS:582 30.     2-(1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)甲氧基)-7-(4-(三氟甲基)吡啶-3-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1407
 MS:599 31.     2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1409
 MS:564 32.     2-(1-丙烯醯基-4-(7-(萘-1-基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1411
 MS:578 33.     2-(1-丙烯醯基-4-(7-(萘-1-基)-2-((3-(吡咯烷-1-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1413
 MS:6061 H NMR (400 MHz, MeOD) δ 8.25 (d, 1H), 7.89 (d, 1H), 7.76 – 7.39 (m, 4H), 7.22 (d, 1H), 6.91 (d, 1H), 6.31 (d, 1H), 5.86 (d, 1H), 5.11 (s, 1H), 4.58 (s, 1H), 4.45 – 4.01 (m, 5H), 3.78 – 3.59 (m, 2H), 3.45 (s, 2H), 3.28 – 3.10 (m, 7H), 3.13 – 2.89 (m, 3H), 2.63 – 2.33 (m, 2H), 2.32 – 1.54 (m, 8H), 1.02 – 0.81 (m, 2H). 34.     2-(1-丙烯醯基-4-(7-(3-氟-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1415
 MS:628 35.     2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1417
 MS:6101 H NMR (400 MHz, MeOD) δ 7.26 – 7.16 (m, 2H), 7.14 – 7.03 (m, 1H), 6.73 (s, 1H), 6.18 (d, 1H), 5.73 (d, 1H), 4.98 (s, 1H), 4.45 (s, 1H), 4.29 – 3.85 (m, 6H), 3.60 – 3.41 (m, 1H), 3.36 – 3.01 (m, 3H), 2.96 – 2.75 (m, 3H), 2.58 (d, 5H), 2.27 – 2.05 (m, 1H), 1.79 – 1.66 (m, 3H), 1.30 – 1.08 (m, 2H), 0.94 – 0.69 (m, 1H), 0.58 (s, 2H), 0.48 (s, 2H). 36.     2-(1-丙烯醯基-4-(2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-7-(2-(三氟甲基)吡啶-3-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1419
 MS:611 37.     2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1421
 MS:5661 H NMR (400 MHz, MeOD) δ 8.14 (d,J = 3.4 Hz, 1H), 7.77 (d,J = 5.1 Hz, 1H), 7.52 (d,J = 8.1 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.34 (d,J = 7.7 Hz, 1H), 7.10 (d,J = 7.3 Hz, 1H), 6.73 (s, 1H), 6.22 (s, 1H), 5.74 (d,J = 10.0 Hz, 1H), 4.15 (d,J = 46.2 Hz, 6H), 2.92 (s, 6H), 2.77 – 2.55 (m, 7H), 1.19 (s, 6H), 0.78 (m, 2H), 0.64 (m, 2H). 38.     2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1423
 MS:644 39.     2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(3-氯-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1425
 MS:6301 H NMR (400 MHz, MeOD) δ 7.45 (t,J = 8.1 Hz, 1H), 7.28 (dt,J = 19.1, 9.6 Hz, 2H), 6.71 (s, 1H), 6.19 (d,J = 16.9 Hz, 1H), 5.73 (d,J = 10.6 Hz, 1H), 4.13 (s, 5H), 3.95 (s, 4H), 3.11 (q,J = 7.3 Hz, 6H), 2.96 – 2.61 (m, 5H), 1.21 (dd,J = 12.6, 5.3 Hz, 5H), 0.72 (m, 4H). 40.     2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(嗎福林甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1427
 MS:660 41.     2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1429
 MS:5781 H NMR (400 MHz, MeOD) δ 8.29 – 8.23 (m, 1H), 7.94 – 7.87 (m, 1H), 7.63 (s, 1H), 7.55 – 7.50 (m, 2H), 7.46 (s, 1H), 7.23 (d,J = 7.4 Hz, 1H), 6.85 (s, 1H), 6.31 (d,J = 16.6 Hz, 1H), 5.86 (d,J = 10.6 Hz, 1H), 4.24 (d,J = 13.7 Hz, 8H), 3.20 (dt,J = 22.4, 11.2 Hz, 3H), 3.13 – 2.90 (m, 4H), 2.50 (s, 2H), 1.32 (dd,J = 15.3, 7.8 Hz, 8H), 0.83 (s, 4H). 42.     2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1431
 MS:612 43.     2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1433
 MS:592 44.     2-(1-丙烯醯基-4-(7-(萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1435
 MS:6061 H NMR (400 MHz, MeOD) δ 8.32 – 8.22 (m, 1H), 7.93 – 7.86 (m, 1H), 7.65 (d,J = 8.2 Hz, 1H), 7.58 – 7.40 (m, 3H), 7.24 (d,J = 7.4 Hz, 1H), 6.97 – 6.77 (m, 1H), 6.33 (d,J = 16.7 Hz, 1H), 5.87 (d,J = 10.6 Hz, 1H), 4.58 (s, 2H), 4.46 – 4.32 (m, 1H), 4.30 – 4.02 (m, 4H), 3.79 – 3.38 (m, 4H), 3.30 – 2.94 (m, 10H), 2.09 (s, 2H), 1.49 – 1.12 (m, 10H). 45.     2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1437
 MS:6201 H NMR (400 MHz, MeOD) δ 7.73 – 7.64 (m, 2H), 7.47 – 7.22 (m, 4H), 7.06 – 6.66 (m, 1H), 6.30 (d,J = 16.3 Hz, 1H), 5.84 (d,J = 10.8 Hz, 1H), 4.62 – 4.51 (m, 2H), 4.33 – 4.23 (m, 1H), 4.20 – 3.99 (m, 2H), 3.83 – 3.44 (m, 3H), 3.25 – 3.06 (m, 6H), 2.92 (s, 3H), 2.84 – 2.66 (m, 2H), 2.12 – 1.91 (m, 13H), 1.31 – 1.27 (m, 4H). 46.     2-(1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1439
 MS:6001 H NMR (400 MHz, MeOD) δ 7.89 (d,J = 8.1 Hz, 1H), 7.74 (d,J = 8.0 Hz, 1H), 7.63 – 7.51 (m, 2H), 7.48 – 7.33 (m, 2H), 7.05 – 6.77 (m, 1H), 6.35 (d,J = 16.9 Hz, 1H), 5.90 (d,J = 10.6 Hz, 1H), 4.49 – 4.08 (m, 6H), 3.92 – 3.43 (m, 4H), 3.29 – 3.12 (m, 3H), 3.04 – 2.90 (m, 1H), 2.86 – 2.66 (m, 1H), 2.66 – 2.44 (m, 2H), 2.32 (s, 6H), 1.47 – 1.27 (m, 2H), 0.82 – 0.66 (m, 2H), 0.65 – 0.45 (m, 2H). 47.     2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1441
 MS:5801 H NMR (400 MHz, MeOD) δ 7.82 – 7.65 (m, 2H), 7.49 – 7.40 (m, 1H), 7.39 – 7.23 (m, 3H), 7.01 – 6.75 (m, 1H), 6.32 (d,J = 16.4 Hz, 1H), 5.86 (d,J = 10.9 Hz, 1H), 4.45 – 3.91 (m, 6H), 3.73 (t,J = 17.5 Hz, 1H), 3.63 – 3.42 (m, 2H), 3.33 – 3.03 (m, 5H), 2.94 (s, 3H), 2.92 – 2.82 (m, 1H), 2.82 – 2.64 (m, 1H), 2.59 – 2.42 (m, 2H), 2.24 (s, 6H), 1.40 – 1.25 (m, 1H), 0.78 – 0.63 (m, 2H), 0.59 – 0.40 (m, 2H). 48.     2-(1-丙烯醯基-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(2,3-二甲基氨基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1443
 MS:5441 H NMR (400 MHz, MeOD) δ 7.10 (t, 1H), 7.03 – 6.94 (m, 2H), 6.93 – 6.77 (m, 1H), 6.32 (d, 1H), 5.86 (d, 1H), 4.31 – 4.13 (m, 4H), 3.95 (s, 2H), 3.34 – 3.08 (m, 7H), 3.07 – 2.80 (m, 4H), 2.45 (s, 2H), 2.32 (m, 12H), 0.71 (t, 2H), 0.53 (t, 2H). 49.     2-(1-丙烯醯基-4-(2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1445
 MS:6241 H NMR (400 MHz, MeOD) δ 7.70 (m, 2H), 7.52 – 7.39 (m, 1H), 7.39 – 7.23 (m, 3H), 7.08 – 6.71 (m, 1H), 6.32 (d, 1H), 5.86 (d, 1H), 4.43 – 4.04 (m, 6H), 3.85 – 3.37 (m, 4H), 3.30 – 2.97 (m, 6H), 2.94 (s, 3H), 2.91 – 2.63 (m, 4H), 2.56 (d, 2H), 2.23 – 1.97 (m, 2H), 1.32 (s, 2H), 0.75 – 0.43 (m, 4H). 50.     2-(1-丙烯醯基-4-(7-(苯并[b]噻吩-7-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1447
 MS:572 51.     2-(1-丙烯醯基-4-(7-(苯并[b]噻吩-4-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1449
 MS:5721 H NMR (400 MHz, MeOD) δ 7.70 – 7.52 (m, 3H), 7.34 (t, 1H), 7.03 (d, 1H), 6.94 – 6.77 (m, 1H), 6.32 (d, 1H), 5.87 (d, 1H), 4.46 – 4.32 (m, 3H), 4.32 – 4.11 (m, 4H), 3.70 – 3.39 (m, 4H), 3.24 – 3.11 (m, 5H), 3.08 – 2.94 (m, 9H), 0.99 – 0.88 (m, 4H). 52.     2-(1-丙烯醯基-4-(7-(苯并[d]噻唑-4-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1451
 MS:573 53.     2-(1-丙烯醯基-4-(7-(2,3-苯并呋喃-7-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1453
 MS:5581 H NMR (400 MHz, MeOD) δ 6.93 (d, 1H), 6.89 – 6.76 (m, 3H), 6.31 (d, 1H), 5.86 (d, 1H), 4.61 (t, 2H), 4.29 – 4.10 (m, 7H), 3.31 – 3.08 (m, 7H), 3.06 – 2.79 (m, 5H), 2.74 – 2.42 (m, 8H), 0.82 – 0.57 (m, 4H). 54.     2-(1-丙烯醯基-4-(7-(苯并[d]噻唑-7-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1455
 MS:5731 H NMR (400 MHz, MeOD) δ 9.15 (s, 1H), 7.67 (d, 1H), 7.42 (t, 1H), 7.08 (d, 1H), 6.99 – 6.75 (m, 1H), 6.31 (d, 1H), 5.86 (d, 1H), 4.47 (m, 2H), 4.34 – 4.11 (m, 4H), 3.93 – 3.67 (m, 2H), 3.41 – 3.27 (m, 4H), 3.26 – 2.92 (m, 5H), 2.51 – 2.24 (m, 8H), 0.80 – 0.49 (m, 4H). 55.     2-(1-丙烯醯基-4-(7-(2-氨基-6-氟苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1457
 MS:549 Using the above procedure or a modified procedure, the following compounds were synthesized from the corresponding starting materials. compound Chemical Name Structural formula MS: (M+H) + / 1 HNMR 2. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(2-methyl-1-oxo- 1,2-Dihydroisoquinolin-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1351
 MS: 597 1 H NMR (400 MHz, MeOD) δ 7.59 – 7.44 (m, 1H), 7.26 (d, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.72 (s, 1H), 6.50 (d, 1H), 6.19 (d, 1H), 5.73 (d, 1H), 4.97 (s, 1H), 4.54 – 4.37 (m, 1H), 4.36 – 3.86 (m, 5H), 3.61 – 3.38 ( m, 4H), 3.19 – 2.81 (m, 8H), 2.81 – 2.58 (m, 6H), 1.35 – 1.02 (m, 3H), 0.86 – 0.55 (m, 4H). 3. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(5-methyl-1H-indazole- 4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1353
 MS:571 4. 2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1355
 MS: 592 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, 1H), 7.78 (d, 1H), 7.43 (ddd, 4H), 7.08 (d, 1H), 6.51 (s, 1H), 6.32 (d, 1H), 5.75 (d, 1H), 5.01 (s, 1H), 4.33 (dd, 6H), 3.90 (s, 2H), 3.57 (s, 1H), 3.47 – 3.00 (m, 6H), 2.82 (s, 5H), 2.24 (s, 2H), 1.96 (s, 2H), 1.21 (d, 2H), 0.89 (s, 2H), 0.79 (s, 2H). 5. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclohexyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1357
 MS: 608 1 H NMR (400 MHz, DMSO) δ 7.76 (d, 1H), 7.70 (d, 1H), 7.46 (dd, 1H), 7.35 (dd, 2H), 7.27 (d, 1H), 6.86 ( s, 1H), 6.19 (d, 1H), 5.78 (d, 1H), 4.01 (dd, 6H), 3.80 – 3.62 (m, 2H), 3.20 – 3.04 (m, 5H), 2.86 (s, 4H) , 2.64 (s, 7H), 2.19 – 1.97 (m, 3H), 1.92 – 1.67 (m, 3H), 1.23 (dd, 26.6 Hz, 6H) 6. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclohexyl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1359
 MS: 612 1 H NMR (400 MHz, DMSO) δ 7.80 – 7.60 (m, 3H), 7.40 (t, 1H), 6.86 (s, 1H), 6.19 (d, 1H), 5.78 (d, 1H), 4.88 (d, 1H), 4.08 (dd, 3H), 4.02 (s, 4H), 3.06 (ddd, 7H), 2.78 (s, 2H), 2.66 (s, 6H), 2.16 (d, 1H), 2.04 (s, 1H), 1.86 (d, 2H), 1.73 (d, 1H), 1.41 – 1.16 (m, 4H), 0.99 (d, 1H). 7. 2-(1-Propenyl-4-(2-(3-(dimethylamino)cyclobutoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyridine [3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1361
 MS:552 8. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclobutyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1363
 MS: 566 1 H NMR (400 MHz, MeOD) δ 8.21 – 8.02 (m, 1H), 7.84 – 7.66 (m, 1H), 7.52 (d, 1H), 7.46 – 7.24 (m, 3H), 7.11 (d , 1H), 6.74 (s, 1H), 6.19 (d, 1H), 5.74 (d, 1H), 4.99 (s, 1H), 4.56 – 4.37 (m, 1H), 4.38 – 3.90 (m, 5H), 3.69 – 3.43 (m, 2H), 3.43 – 3.07 (m, 4H), 3.05 – 2.68 (m, 6H), 2.64 – 2.24 (m, 8H), 2.08 – 1.90 (m, 2H). 9. 2-(1-Propenyl-4-(2-((1-(dimethylamino)cyclobutyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1365
 MS: 566 1 H NMR (400 MHz, MeOD) δ 8.33 – 8.19 (m, 1H), 7.96 – 7.82 (m, 1H), 7.71 – 7.59 (m, 1H), 7.57 – 7.36 (m, 3H), 7.23 (d, 1H), 6.84 (s, 1H), 6.32 (d, 1H), 5.84 (d, 1H), 5.10 (s, 1H), 4.58 (s, 1H), 4.42 (d, 1H), 4.33 – 4.06 (m, 4H), 3.77 – 3.35 (m, 4H), 3.21 – 2.90 (m, 4H), 2.84 (s, 6H), 2.54 – 2.23 (m, 4H), 2.10 – 1.92 (m, 2H), 1.43 – 1.22 (m, 2H). 10. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclohexyl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1367
 MS: 578 1 H NMR (400 MHz, MeOD) δ 8.20 – 8.06 (m, 1H), 7.82 – 7.71 (m, 1H), 7.51 (d, 1H), 7.46 – 7.27 (m, 3H), 7.10 (d , 1H), 6.72 (s, 1H), 6.20 (d, 1H), 5.74 (d, 1H), 4.98 (s, 1H), 4.22 – 3.89 (m, 4H), 3.53 (s, 1H), 3.44 – 3.27 (m, 2H), 3.27 – 2.78 (m, 7H), 2.74 – 2.58 (m, 5H), 2.53 – 2.35 (m, 1H), 2.10 (d, 1H), 2.02 – 1.82 (m, 2H), 1.64 – 1.30 (m, 4H), 1.27 – 1.09 (m, 3H). 11. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclohexyl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1369
 MS:580 12. 2-(1-Propenyl-4-(2-((1-(dimethylamino)cyclopropyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1371
 MS:552 13. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)oxy)-7-(naphthalen-1-yl)-5,6,7,8- Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1373
 MS:566 14. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1375
 MS: 580 1 H NMR (400 MHz, DMSO) δ 8.38 – 8.10 (m, 1H), 8.06 – 7.86 (m, 1H), 7.65 (d, 1H), 7.61–7.40 (m, 3H), 7.23 (d , 1H), 6.88 (s, 1H), 6.20 (d, 1H), 5.79 (d, 1H), 4.88 (d, 1H), 4.69 – 4.24 (m, 2H), 4.10 (d, 5H), 3.66 – 3.37 (m, 2H), 3.21 (s, 3H), 3.00 (d, 6H), 2.74 (d, 2H), 2.26 (d, 4H), 1.72 (d, 5H), 1.20 (d, 1H). 15. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclohexyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8- Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1377
 MS: 594, 1 H NMR (400 MHz, MeOD) δ 8.34 – 8.17 (m, 1H), 7.96 – 7.84 (m, 1H), 7.63 (d, 1H), 7.58 – 7.37 (m, 3H), 7.22 ( d, 1H), 6.83 (s, 1H), 6.31 (d, 1H), 5.85 (d, 1H), 5.10 (s, 1H), 4.40 – 4.01 (m, 6H), 3.66 (s, 1H), 3.44 (s, 2H), 3.34 – 3.22 (m, 2H), 3.20 – 2.92 (m, 4H), 2.87 (s, 6H), 2.28 (d, 1H), 2.18 – 1.96 (m, 3H), 1.90 (d , 1H), 1.59 – 1.07 (m, 6H). 16. 2-(1-Propenyl-4-(2-((2-(4-methylpiperidin-1-yl)cyclopentyl)oxy)-7-(naphthalen-1-yl)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1379
 MS:621 17. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1381
 MS: 580 1 H NMR (400 MHz, MeOD) δ 8.24 (d, 1H), 7.87 (d, 1H), 7.61 (d, 1H), 7.56 – 7.47 (m, 2H), 7.44 (t, 1H), 7.21 (d, 1H), 6.82 (s, 1H), 6.30 (d, 1H), 5.85 (d, 1H), 4.38 – 4.07 (m, 7H), 3.77 – 3.57 (m, 1H), 3.52 – 3.40 ( m, 1H), 3.12 – 2.83 (m, 4H), 2.72 – 2.57 (m, 1H), 2.52 – 2.40 (m, 1H), 2.31 (s, 6H), 2.23 – 2.10 (m, 1H), 2.05 – 1.82 (m, 2H), 1.81 – 1.67 (m, 1H), 1.66 – 1.40 (m, 3H), 1.39 – 1.17 (m, 2H), 1.05 – 0.95 (m, 1H). 18. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclohexyl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8- Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1383
 MS: 594 1 H NMR (400 MHz, MeOD) δ 8.21 – 8.06 (m, 1H), 7.85 – 7.69 (m, 1H), 7.52 (d, 1H), 7.46 – 7.24 (m, 3H), 7.10 (d , 1H), 6.72 (s, 1H), 6.20 (d, 1H), 5.74 (d, 1H), 4.99 (s, 1H), 4.57 – 4.40 (m, 2H), 4.22 (d, 1H), 4.16 – 3.90 (m, 3H), 3.53 (s, 1H), 3.33 (s, 2H), 3.27 – 3.05 (m, 2H), 2.87 (d, 5H), 2.75 (s, 6H), 2.16 – 1.75 (m, 4H), 1.68 – 1.28 (m, 6H). 19. 2-(1-Propenyl-4-(2-((2-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(naphthalen-1-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1385
 MS:566 20. 2-(1-Propenyl-4-(2-((1-(dimethylamino)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1387
 MS: 566 1 H NMR (400 MHz, MeOD) δ 7.67 – 7.48 (m, 2H), 7.39 – 7.26 (m, 1H), 7.26 – 7.08 (m, 3H), 6.70 (s, 1H), 6.19 (d , 1H), 5.00 (s, 1H), 4.47 (s, 1H), 4.33 (s, 2H), 4.21 (d, 1H), 4.14 – 3.89 (m, 3H), 3.69 – 3.49 (m, 1H), 3.48 – 3.27 (m, 2H), 3.18 – 2.90 (m, 4H), 2.86 – 2.75 (m, 4H), 2.63 (d, 1H), 2.38 (d, 6H), 2.32 – 2.19 (m, 1H), 0.90 – 0.54 (m, 4H). twenty one. 2-(1-Propenyl-4-(2-(2-(2-(dimethylamino)cyclopentyl)ethoxy)-7-(naphthalen-1-yl)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1389
 MS: 594 1 H NMR (400 MHz, MeOD) δ 8.13 (d, 1H), 7.84 – 7.67 (m, 1H), 7.58 – 7.48 (m, 1H), 7.47 – 7.24 (m, 3H), 7.10 (d , 1H), 6.72 (s, 1H), 6.19 (d, 1H), 5.74 (d, 1H), 4.99 (s, 1H), 4.52 – 4.36 (m, 1H), 4.29 (s, 1H), 4.19 ( s, 1H), 4.13 – 3.87 (m, 3H), 3.42 – 3.26 (m, 2H), 3.17 – 2.77 (m, 6H), 2.70 – 2.52 (m, 4H), 2.43 – 2.29 (m, 1H), 2.14 – 1.90 (m, 3H), 1.89 – 1.61 (m, 5H), 1.61 – 1.34 (m, 3H), 0.86 – 0.72 (m, 2H). twenty two. 2-(1-Propenyl-4-(2-(((1R,3S)-3-(dimethylamino)cyclopentyl)methoxy)-7-(8-methylnaphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1391
 MS: 594 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 – 7.55 (m, 2H), 7.45 – 7.17 (m, 4H), 6.55 (s, 1H), 6.32 (d, 1H), 5.75 (d, 1H), 4.19 (dd, 4H), 3.36 (d, 3H), 3.11 – 3.00 (m, 5H), 2.84 (s, 3H), 2.72 (s, 7H), 1.32 (dd, 5H), 1.25 (s , 5H), 0.80 (d, 2H) twenty three. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1393
 MS: 594 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 – 7.52 (m, 2H), 7.31 (ddd, 3H), 7.19 – 7.14 (m, 1H), 6.56 (s, 1H), 6.31 (d, 1H), 5.72 (d, 1H), 4.95 (s, 1H), 4.70 (s, 2H), 4.34 –3.91 (m, 4H), 3.80 – 3.57 (m, 2H), 3.43 (s, 2H), 3.23 (s, 2H), 3.10 (s, 2H), 2.85 (s, 5H), 2.74 (d, 5H), 2.56 (d, 1H), 2.23 – 1.88 (m, 4H), 1.72 (s, 2H), 1.29 – 1.13 (m, 2H). twenty four. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1395
 MS: 594 1 H NMR (400 MHz, MeOD) δ 7.71 (dd, 4.7 Hz, 2H), 7.48 – 7.41 (m, 1H), 7.38 – 7.32 (m, 2H), 7.31 – 7.23 (m, 1H), 6.91 – 6.73 (m, 1H), 6.31 (d, 1H), 5.85 (d, 1H), 5.15 – 4.93 (m, 1H), 4.68 – 4.37 (m, 4H), 4.25 – 4.04 (m, 2H), 3.95 – 3.80 (m, 2H), 3.72 – 3.47 (m, 4H), 3.28 – 3.17 (m, 2H), 3.11 – 3.03 (m, 1H), 2.93 (d, 3H), 2.90 (s, 6H), 2.79 – 2.68 (m, 1H), 2.66 – 2.49 (m, 1H), 2.46 – 2.35 (m, 1H), 2.27 – 2.15 (m, 1H), 2.06 – 1.50 (m, 5H). 25. 2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((2-(dimethylamino)cyclopentyl)methoxy)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1397
 MS: 598 1 H NMR (400 MHz, CDCl 3 ) δ 7.12 (q, 2H), 6.93 (d, 1H), 6.54 (s, 1H), 6.30 (d, 1H), 5.72 (d, 1H), 4.96 (s, 1H), 4.74 (s, 2H), 4.34 – 3.78 (m, 5H), 3.33 (dd, 5H), 3.11 (s, 1H), 2.86 (d, 7H), 2.71 (s, 2H), 2.13 (s, 3H), 1.94 (s, 1H), 1.74 (s, 2H), 1.19 (s, 2H) 26. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(3-fluoro-2-(trifluoromethyl)phenyl) )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1399
 MS: 616 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (dd, 1H), 7.07 (d, 1H), 7.02 – 6.90 (m, 1H), 6.65 (s, 1H), 6.39 (d, 1H) , 5.81 (d, 1H), 5.05 (s, 1H), 4.84 (s, 2H), 4.25 (dd, 2H), 4.12 (s, 3H), 3.37 (dd, 5H), 3.18 (s, 1H), 2.94 (d, 7H), 2.80 (s, 2H), 2.18 (dd, 4H), 1.83 (s, 2H), 1.35 – 1.21 (m, 2H) 27. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1401
 MS: 598 1 H NMR (400 MHz, MeOD) δ 7.70 – 7.52 (m, 2H), 7.52 – 7.43 (m, 1H), 7.35 – 7.20 (m, 1H), 6.71 (s, 1H), 6.19 (d , 1H), 5.80 – 5.66 (m, 1H), 5.00 (s, 1H), 4.44 – 4.30 (m, 1H), 4.25 – 3.97 (m, 3H), 3.90 (s, 2H), 3.53 (s, 1H) ), 3.16 – 2.99 (m, 3H), 2.91 (s, 2H), 2.77 (s, 2H), 2.59 (d, 3H), 2.40 (s, 6H), 2.02 – 1.41 (m, 7H). 28. 2-(1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(2,3-dimethylamino)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1403
 MS:558 29. 2-(1-Propenyl-4-(7-(2-chloro-3-fluorophenyl)-2-((3-(dimethylamino)cyclopentyl)methoxy)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1405
 MS:582 30. 2-(1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)methoxy)-7-(4-(trifluoromethyl)pyridin-3-yl) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1407
 MS:599 31. 2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((3-(dimethylamino)cyclopentyl)methoxy)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1409
 MS:564 32. 2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1411
 MS:578 33. 2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-((3-(pyrrolidin-1-yl)cyclopentyl)methoxy)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1413
 MS: 606 1 H NMR (400 MHz, MeOD) δ 8.25 (d, 1H), 7.89 (d, 1H), 7.76 – 7.39 (m, 4H), 7.22 (d, 1H), 6.91 (d, 1H), 6.31 (d, 1H), 5.86 (d, 1H), 5.11 (s, 1H), 4.58 (s, 1H), 4.45 – 4.01 (m, 5H), 3.78 – 3.59 (m, 2H), 3.45 (s, 2H), 3.28 – 3.10 (m, 7H), 3.13 – 2.89 (m, 3H), 2.63 – 2.33 (m, 2H), 2.32 – 1.54 (m, 8H), 1.02 – 0.81 (m, 2H). 34. 2-(1-Propenyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1415
 MS:628 35. 2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1417
 MS: 610 1 H NMR (400 MHz, MeOD) δ 7.26 – 7.16 (m, 2H), 7.14 – 7.03 (m, 1H), 6.73 (s, 1H), 6.18 (d, 1H), 5.73 (d, 1H) ), 4.98 (s, 1H), 4.45 (s, 1H), 4.29 – 3.85 (m, 6H), 3.60 – 3.41 (m, 1H), 3.36 – 3.01 (m, 3H), 2.96 – 2.75 (m, 3H) ), 2.58 (d, 5H), 2.27 – 2.05 (m, 1H), 1.79 – 1.66 (m, 3H), 1.30 – 1.08 (m, 2H), 0.94 – 0.69 (m, 1H), 0.58 (s, 2H) ), 0.48 (s, 2H). 36. 2-(1-Propenyl-4-(2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-7-(2-(trifluoromethyl)pyridine- 3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1419
 MS:611 37. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(naphthalen-1-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1421
 MS: 566 1 H NMR (400 MHz, MeOD) δ 8.14 (d, J = 3.4 Hz, 1H), 7.77 (d, J = 5.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.34 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.3 Hz, 1H), 6.73 (s, 1H), 6.22 (s, 1H), 5.74 (d, J = 10.0 Hz, 1H), 4.15 (d, J = 46.2 Hz, 6H), 2.92 (s, 6H), 2.77 – 2.55 (m, 7H), 1.19 (s, 6H), 0.78 (m, 2H), 0.64 (m, 2H). 38. 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1423
 MS:644 39. 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(3-chloro-2-( Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1425
 MS: 630 1 H NMR (400 MHz, MeOD) δ 7.45 (t, J = 8.1 Hz, 1H), 7.28 (dt, J = 19.1, 9.6 Hz, 2H), 6.71 (s, 1H), 6.19 (d, J = 16.9 Hz, 1H), 5.73 (d, J = 10.6 Hz, 1H), 4.13 (s, 5H), 3.95 (s, 4H), 3.11 (q, J = 7.3 Hz, 6H), 2.96 – 2.61 ( m, 5H), 1.21 (dd, J = 12.6, 5.3 Hz, 5H), 0.72 (m, 4H). 40. 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(mfolinmethyl)cyclopropyl)methoxy) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1427
 MS:660 41. 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(naphthalen-1-yl)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1429
 MS: 578 1 H NMR (400 MHz, MeOD) δ 8.29 – 8.23 (m, 1H), 7.94 – 7.87 (m, 1H), 7.63 (s, 1H), 7.55 – 7.50 (m, 2H), 7.46 (s , 1H), 7.23 (d, J = 7.4 Hz, 1H), 6.85 (s, 1H), 6.31 (d, J = 16.6 Hz, 1H), 5.86 (d, J = 10.6 Hz, 1H), 4.24 (d , J = 13.7 Hz, 8H), 3.20 (dt, J = 22.4, 11.2 Hz, 3H), 3.13 – 2.90 (m, 4H), 2.50 (s, 2H), 1.32 (dd, J = 15.3, 7.8 Hz, 8H), 0.83 (s, 4H). 42. 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-chloronaphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1431
 MS:612 43. 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-methylnaphthalene-1 -yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1433
 MS:592 44. 2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclobutyl)methoxy)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1435
 MS: 606 1 H NMR (400 MHz, MeOD) δ 8.32 – 8.22 (m, 1H), 7.93 – 7.86 (m, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.58 – 7.40 (m, 3H) ), 7.24 (d, J = 7.4 Hz, 1H), 6.97 – 6.77 (m, 1H), 6.33 (d, J = 16.7 Hz, 1H), 5.87 (d, J = 10.6 Hz, 1H), 4.58 (s , 2H), 4.46 – 4.32 (m, 1H), 4.30 – 4.02 (m, 4H), 3.79 – 3.38 (m, 4H), 3.30 – 2.94 (m, 10H), 2.09 (s, 2H), 1.49 – 1.12 (m, 10H). 45. 2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclobutyl)methoxy) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1437
 MS: 620 1 H NMR (400 MHz, MeOD) δ 7.73 – 7.64 (m, 2H), 7.47 – 7.22 (m, 4H), 7.06 – 6.66 (m, 1H), 6.30 (d, J = 16.3 Hz, 1H ), 5.84 (d, J = 10.8 Hz, 1H), 4.62 – 4.51 (m, 2H), 4.33 – 4.23 (m, 1H), 4.20 – 3.99 (m, 2H), 3.83 – 3.44 (m, 3H), 3.25 – 3.06 (m, 6H), 2.92 (s, 3H), 2.84 – 2.66 (m, 2H), 2.12 – 1.91 (m, 13H), 1.31 – 1.27 (m, 4H). 46. 2-(1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1439
 MS: 600 1 H NMR (400 MHz, MeOD) δ 7.89 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 – 7.51 (m, 2H), 7.48 – 7.33 ( m, 2H), 7.05 – 6.77 (m, 1H), 6.35 (d, J = 16.9 Hz, 1H), 5.90 (d, J = 10.6 Hz, 1H), 4.49 – 4.08 (m, 6H), 3.92 – 3.43 (m, 4H), 3.29 – 3.12 (m, 3H), 3.04 – 2.90 (m, 1H), 2.86 – 2.66 (m, 1H), 2.66 – 2.44 (m, 2H), 2.32 (s, 6H), 1.47 – 1.27 (m, 2H), 0.82 – 0.66 (m, 2H), 0.65 – 0.45 (m, 2H). 47. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1441
 MS: 580 1 H NMR (400 MHz, MeOD) δ 7.82 – 7.65 (m, 2H), 7.49 – 7.40 (m, 1H), 7.39 – 7.23 (m, 3H), 7.01 – 6.75 (m, 1H), 6.32 (d, J = 16.4 Hz, 1H), 5.86 (d, J = 10.9 Hz, 1H), 4.45 – 3.91 (m, 6H), 3.73 (t, J = 17.5 Hz, 1H), 3.63 – 3.42 (m, 2H), 3.33 – 3.03 (m, 5H), 2.94 (s, 3H), 2.92 – 2.82 (m, 1H), 2.82 – 2.64 (m, 1H), 2.59 – 2.42 (m, 2H), 2.24 (s, 6H), 1.40 – 1.25 (m, 1H), 0.78 – 0.63 (m, 2H), 0.59 – 0.40 (m, 2H). 48. 2-(1-Propenyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(2,3-dimethylamino)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1443
 MS: 544 1 H NMR (400 MHz, MeOD) δ 7.10 (t, 1H), 7.03 – 6.94 (m, 2H), 6.93 – 6.77 (m, 1H), 6.32 (d, 1H), 5.86 (d, 1H) ), 4.31 – 4.13 (m, 4H), 3.95 (s, 2H), 3.34 – 3.08 (m, 7H), 3.07 – 2.80 (m, 4H), 2.45 (s, 2H), 2.32 (m, 12H), 0.71 (t, 2H), 0.53 (t, 2H). 49. 2-(1-Propenyl-4-(2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8 -Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1445
 MS: 624 1 H NMR (400 MHz, MeOD) δ 7.70 (m, 2H), 7.52 – 7.39 (m, 1H), 7.39 – 7.23 (m, 3H), 7.08 – 6.71 (m, 1H), 6.32 (d , 1H), 5.86 (d, 1H), 4.43 – 4.04 (m, 6H), 3.85 – 3.37 (m, 4H), 3.30 – 2.97 (m, 6H), 2.94 (s, 3H), 2.91 – 2.63 (m , 4H), 2.56 (d, 2H), 2.23 – 1.97 (m, 2H), 1.32 (s, 2H), 0.75 – 0.43 (m, 4H). 50. 2-(1-Propenyl-4-(7-(benzo[b]thiophen-7-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1447
 MS:572 51. 2-(1-Propenyl-4-(7-(benzo[b]thiophen-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1449
 MS: 572 1 H NMR (400 MHz, MeOD) δ 7.70 – 7.52 (m, 3H), 7.34 (t, 1H), 7.03 (d, 1H), 6.94 – 6.77 (m, 1H), 6.32 (d, 1H) ), 5.87 (d, 1H), 4.46 – 4.32 (m, 3H), 4.32 – 4.11 (m, 4H), 3.70 – 3.39 (m, 4H), 3.24 – 3.11 (m, 5H), 3.08 – 2.94 (m , 9H), 0.99 – 0.88 (m, 4H). 52. 2-(1-Propenyl-4-(7-(benzo[d]thiazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1451
 MS:573 53. 2-(1-Propenyl-4-(7-(2,3-benzofuran-7-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1453
 MS: 558 1 H NMR (400 MHz, MeOD) δ 6.93 (d, 1H), 6.89 – 6.76 (m, 3H), 6.31 (d, 1H), 5.86 (d, 1H), 4.61 (t, 2H), 4.29 – 4.10 (m, 7H), 3.31 – 3.08 (m, 7H), 3.06 – 2.79 (m, 5H), 2.74 – 2.42 (m, 8H), 0.82 – 0.57 (m, 4H). 54. 2-(1-Propenyl-4-(7-(benzo[d]thiazol-7-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1455
 MS: 573 1 H NMR (400 MHz, MeOD) δ 9.15 (s, 1H), 7.67 (d, 1H), 7.42 (t, 1H), 7.08 (d, 1H), 6.99 – 6.75 (m, 1H), 6.31 (d, 1H), 5.86 (d, 1H), 4.47 (m, 2H), 4.34 – 4.11 (m, 4H), 3.93 – 3.67 (m, 2H), 3.41 – 3.27 (m, 4H), 3.26 – 2.92 (m, 5H), 2.51 – 2.24 (m, 8H), 0.80 – 0.49 (m, 4H). 55. 2-(1-Propenyl-4-(7-(2-amino-6-fluorophenyl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1457
 MS:549

實施例56

Figure 02_image1459
Example 56
Figure 02_image1459

步驟a：向中間體D1 (87 mg, 0.13 mmol)的DCM(10 mL)溶液中加入TFA (1 mL)。反應混合物於25℃攪拌3小時。反應結束，體系減壓濃縮。殘餘物溶於DCM (10 mL)。向溶液中加入三乙胺(0.5 mL)和丙烯醯氯(46 mg, 0.51 mmol)，然後混合物於25℃攪拌40分鐘。反應結束，反應體系減壓濃縮。殘餘物以製備薄層色譜法(DCM: MeOH = 10:1，v/v洗脫)純化，得到黃色固體化合物56 (34 mg)。MS: m/z 606 [M+H]+ ，1 H NMR (400 MHz,DMSO-d6 ) δ 7.76 (d, 1H), 7.73 – 7.66 (m, 1H), 7.52 – 7.41 (m, 1H), 7.41 – 7.24 (m, 3H), 6.94 – 6.77 (m, 1H), 6.19 (d, 1H), 5.78 (d, 1H), 4.10 (d, 2H), 4.08 – 3.79 (m, 4H), 3.79 – 3.55 (m, 2H), 3.42 (d, 2H), 3.29 – 3.16 (m, 2H), 3.16 – 3.02 (m, 4H), 2.98 – 2.89 (m, 1H), 2.86 (s, 3H), 2.81 – 2.57 (m, 2H), 2.47 – 2.24 (m, 4H), 1.81 – 1.49 (m, 4H), 0.70 – 0.22 (m, 4H)。Step a: To a solution of Intermediate D1 (87 mg, 0.13 mmol) in DCM (10 mL) was added TFA (1 mL). The reaction mixture was stirred at 25°C for 3 hours. After the reaction was completed, the system was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL). To the solution were added triethylamine (0.5 mL) and acryl chloride (46 mg, 0.51 mmol), and then the mixture was stirred at 25°C for 40 minutes. After the reaction was completed, the reaction system was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM:MeOH = 10:1, v/v elution) to give compound 56 (34 mg) as a yellow solid. MS: m/z 606 [M+H] + , 1 H NMR (400 MHz, DMSO-d6 ) δ 7.76 (d, 1H), 7.73 – 7.66 (m, 1H), 7.52 – 7.41 (m, 1H), 7.41 – 7.24 (m, 3H), 6.94 – 6.77 (m, 1H), 6.19 (d, 1H), 5.78 (d, 1H), 4.10 (d, 2H), 4.08 – 3.79 (m, 4H), 3.79 – 3.55 (m, 2H), 3.42 (d, 2H), 3.29 – 3.16 (m, 2H), 3.16 – 3.02 (m, 4H), 2.98 – 2.89 (m, 1H), 2.86 (s, 3H), 2.81 – 2.57 (m, 2H), 2.47 – 2.24 (m, 4H), 1.81 – 1.49 (m, 4H), 0.70 – 0.22 (m, 4H).

使用上述工藝或修改工藝，以相應的原料合成了以下化合物。 化合物 化學名稱 結構式 MS: (M+H)+ /1 HNMR 57       2-(1-丙烯醯基-4-(2-(1-(1-((二甲基氨基)甲基)環丙基)乙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈

Figure 02_image1460
MS:5941 H NMR (400 MHz, MeOD) δ 7.80 – 7.58 (m, 2H), 7.43 (m, 1H), 7.37 – 7.19 (m, 3H), 6.83 (s, 1H), 6.38 – 6.22 (m, 1H), 5.85 (d, 1H), 5.22 – 5.01 (m, 1H), 4.59 (s, 1H), 4.40 – 3.97 (m, 4H), 3.80 – 3.62 (m, 2H), 3.65 – 3.41 (m, 2H), 3.29 – 3.06 (m, 4H), 2.93 (m, 4H), 2.84 – 2.65 (m, 2H), 2.61 – 2.09 (m, 7H), 1.46 – 1.27 (m, 3H), 0.77 (d, 2H), 0.43 (s, 2H). 58       2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-((4-甲基哌嗪-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1462
 MS:6351 H NMR (400 MHz, MeOD) δ 7.78 – 7.60 (m, 2H), 7.49 – 7.39 (m, 1H), 7.37 – 7.18 (m, 3H), 6.85 (s, 1H), 6.31 (d, 1H), 5.91 – 5.76 (m, 1H), 5.08 (s, 1H), 4.58 (s, 1H), 4.39 – 4.00 (m, 5H), 3.89 – 3.65 (m, 2H), 3.63 – 3.42 (m, 2H), 3.28 – 2.97 (m, 6H), 2.97 – 2.82 (m, 4H), 2.80 – 2.35 (m, 9H), 2.28 (d, 3H), 0.67 (s, 2H), 0.50 (d, 2H). 59       2-(1-丙烯醯基-4-(2-((1-((3-(二甲基氨基)氮雜環丁烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1464
 MS:635 60       2-(1-丙烯醯基-4-(2-(((1S,2S)-2-(二甲基氨基)環己基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1466
 MS:5801 H NMR (400 MHz, MeOD) δ 8.31 – 8.19 (m, 1H), 7.98 – 7.82 (m, 1H), 7.71 – 7.59 (m, 1H), 7.59 – 7.38 (m, 3H), 7.29 – 7.17 (m, 1H), 6.84 (s, 1H), 6.31 (d, 1H), 5.86 (d, 1H), 5.09 (s, 1H), 4.59 (s, 1H), 4.40 – 3.99 (m, 5H), 3.76 – 3.36 (m, 4H), 3.20 – 2.88 (m, 4H), 2.79 (s, 6H), 2.39 (s, 1H), 2.22 – 2.08 (m, 1H), 1.99 – 1.75 (m, 2H), 1.74 – 1.57 (m, 1H), 1.59 – 1.20 (m, 5H). 61       2-(1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1468
 MS:6261 H NMR (400 MHz, MeOD) δ 7.75 (d,J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.45 (d,J = 7.5 Hz, 2H), 7.30 (d,J = 7.8 Hz, 2H), 6.74 (s, 1H), 6.21 (d,J = 16.8 Hz, 1H), 5.75 (d,J = 10.9 Hz, 1H), 4.99 (s, 1H), 4.39 (d,J = 84.3 Hz, 1H), 4.35 – 4.11 (m, 4H), 4.17 – 3.83 (m, 3H), 3.76 – 3.56 (m, 2H), 3.52 (s, 1H), 3.41 (s, 1H), 3.13 (s, 4H), 2.63 (s, 6H), 1.76 (s, 4H), 0.61 (s, 2H), 0.48 (s, 2H). 62       2-(1-丙烯醯基-4-(2-((1-((3-氟氮雜環丁烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1470
 MS:6101 H NMR (400 MHz, MeOD) δ 7.58 (d,J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.30 (d,J = 5.5 Hz, 1H), 7.20 (d,J = 7.7 Hz, 2H), 7.15 (s, 1H), 6.73 (s, 1H), 6.19 (d,J = 16.4 Hz, 1H), 5.73 (d,J = 10.4 Hz, 1H), 4.99 (d,J = 57.6 Hz, 2H), 4.16 – 4.01 (m, 3H), 3.97 (d,J = 10.2 Hz, 2H), 3.68 – 3.52 (m, 3H), 3.48 – 3.30 (m, 2H), 3.19 – 2.94 (m, 7H), 2.81 (s, 4H), 2.59 (dd,J = 30.3, 15.3 Hz, 2H), 2.51 (d,J = 12.7 Hz, 2H), 0.48 (d,J = 3.5 Hz, 2H), 0.41 (s, 2H). 63       2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-(4-甲基哌嗪-1-羰基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1472
 MS:649 64       2-(1-丙烯醯基-4-(2-((1-(((2-(二甲基氨基)乙基)(甲基)氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1474
 MS:6371 H NMR (400 MHz, MeOD) δ 7.79 – 7.63 (m, 2H), 7.48 – 7.40 (m, 1H), 7.39 – 7.19 (m, 3H), 6.97 – 6.74 (m, 1H), 6.32 (d,J = 16.6 Hz, 1H), 5.86 (d,J = 10.5 Hz, 1H), 4.46 – 3.93 (m, 6H), 3.76 - 3.51 (m, 4H), 3.30 – 3.05 (m, 5H), 2.94 (s, 3H), 2.92 – 2.85 (m, 1H), 2.83 – 2.65 (m, 1H), 2.64 – 2.53 (m, 4H), 2.53 – 2.38 (m, 2H), 2.37 – 2.24 (m, 8H), 1.47 – 1.27 (m, 1H), 0.74 – 0.62 (m, 2H), 0.58 – 0.43 (m, 2H). 65       2-(1-丙烯醯基-4-(2-((1-(((S)-3-(二甲基氨基)吡咯烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1476
 MS:6491 H NMR (400 MHz, MeOD) δ 7.78 – 7.62 (m, 2H), 7.48 – 7.40 (m, 1H), 7.38 – 7.21 (m, 3H), 6.96 – 6.76 (m, 1H), 6.32 (d,J = 16.5 Hz, 1H), 5.86 (d,J = 10.4 Hz, 1H), 4.43 – 4.02 (m, 6H), 3.86 – 3.64 (m, 2H), 3.61 – 3.41 (m, 2H), 3.30 – 3.05 (m, 5H), 2.94 (s, 3H), 2.91 – 2.86 (m, 1H), 2.81 – 2.72 (m, 2H), 2.70 – 2.43 (m, 4H), 2.25 (s, 6H), 2.12 – 1.93 (m, 1H), 1.85 – 1.69 (m, 1H), 1.41 – 1.25 (m, 2H), 0.74 – 0.62 (m, 2H), 0.57 – 0.48 (m, 2H). 66       2-(4-(2-((1-((4-乙醯基哌嗪-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-丙烯醯基哌嗪-2-基)乙腈
Figure 02_image1478
 MS:6631 H NMR (400 MHz, MeOD) δ 7.75 – 7.63 (m, 2H), 7.48 – 7.40 (m, 1H), 7.39 – 7.22 (m, 3H), 6.99 – 6.75 (m, 1H), 6.32 (d,J = 17.0 Hz, 1H), 5.86 (d,J = 10.3 Hz, 1H), 4.44 – 4.03 (m, 6H), 3.80 – 3.65 (m, 1H), 3.64 – 3.42 (m, 6H), 3.34 – 3.07 (m, 6H), 2.94 (s, 3H), 2.93 – 2.86 (m, 1H), 2.83 – 2.66 (m, 1H), 2.61 – 2.37 (m, 6H), 2.10 (s, 3H), 0.77 – 0.62 (m, 2H), 0.55 – 0.42 (m, 2H). 67       (S)-2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1480
 MS:6061 H NMR (400 MHz, MeOD) δ 7.74 – 7.65 (m, 2H), 7.48 – 7.39 (m, 1H), 7.38 – 7.25 (m, 3H), 6.99 – 6.76 (m, 1H), 6.32 (d, 1H), 5.86 (d, 1H), 4.39 – 4.05 (m, 6H), 3.72 (t, 1H), 3.62 – 3.43 (m, 2H), 3.30 – 3.05 (m, 5H), 3.03 – 2.88 (m, 4H), 2.85 – 2.49 (m, 8H), 1.91 – 1.68 (m, 4H), 0.74 – 0.48 (m, 4H). Using the above procedure or a modified procedure, the following compounds were synthesized from the corresponding starting materials. compound Chemical Name Structural formula MS: (M+H) + / 1 HNMR 57 2-(1-Propenyl-4-(2-(1-(1-((dimethylamino)methyl)cyclopropyl)ethoxy)-7-(8-methylnaphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1460
 MS: 594 1 H NMR (400 MHz, MeOD) δ 7.80 – 7.58 (m, 2H), 7.43 (m, 1H), 7.37 – 7.19 (m, 3H), 6.83 (s, 1H), 6.38 – 6.22 (m , 1H), 5.85 (d, 1H), 5.22 – 5.01 (m, 1H), 4.59 (s, 1H), 4.40 – 3.97 (m, 4H), 3.80 – 3.62 (m, 2H), 3.65 – 3.41 (m , 2H), 3.29 – 3.06 (m, 4H), 2.93 (m, 4H), 2.84 – 2.65 (m, 2H), 2.61 – 2.09 (m, 7H), 1.46 – 1.27 (m, 3H), 0.77 (d , 2H), 0.43 (s, 2H). 58 2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-((4-methylpiperazin-1-yl)methyl)cyclopropane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1462
 MS: 635 1 H NMR (400 MHz, MeOD) δ 7.78 – 7.60 (m, 2H), 7.49 – 7.39 (m, 1H), 7.37 – 7.18 (m, 3H), 6.85 (s, 1H), 6.31 (d , 1H), 5.91 – 5.76 (m, 1H), 5.08 (s, 1H), 4.58 (s, 1H), 4.39 – 4.00 (m, 5H), 3.89 – 3.65 (m, 2H), 3.63 – 3.42 (m , 2H), 3.28 – 2.97 (m, 6H), 2.97 – 2.82 (m, 4H), 2.80 – 2.35 (m, 9H), 2.28 (d, 3H), 0.67 (s, 2H), 0.50 (d, 2H) ). 59 2-(1-Propenyl-4-(2-((1-((3-(dimethylamino)azetidin-1-yl)methyl)cyclopropyl)methoxy)- 7-(8-Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1464
 MS:635 60 2-(1-Propenyl-4-(2-(((1S,2S)-2-(dimethylamino)cyclohexyl)oxy)-7-(naphthalen-1-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1466
 MS: 580 1 H NMR (400 MHz, MeOD) δ 8.31 – 8.19 (m, 1H), 7.98 – 7.82 (m, 1H), 7.71 – 7.59 (m, 1H), 7.59 – 7.38 (m, 3H), 7.29 – 7.17 (m, 1H), 6.84 (s, 1H), 6.31 (d, 1H), 5.86 (d, 1H), 5.09 (s, 1H), 4.59 (s, 1H), 4.40 – 3.99 (m, 5H) ), 3.76 – 3.36 (m, 4H), 3.20 – 2.88 (m, 4H), 2.79 (s, 6H), 2.39 (s, 1H), 2.22 – 2.08 (m, 1H), 1.99 – 1.75 (m, 2H) ), 1.74 – 1.57 (m, 1H), 1.59 – 1.20 (m, 5H). 61 2-(1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1468
 MS: 626 1 H NMR (400 MHz, MeOD) δ 7.75 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 6.74 (s, 1H), 6.21 (d, J = 16.8 Hz, 1H), 5.75 (d, J = 10.9 Hz, 1H), 4.99 (s, 1H), 4.39 (d, J = 84.3 Hz, 1H), 4.35 – 4.11 (m, 4H), 4.17 – 3.83 (m, 3H), 3.76 – 3.56 (m, 2H), 3.52 (s, 1H), 3.41 (s, 1H), 3.13 (s , 4H), 2.63 (s, 6H), 1.76 (s, 4H), 0.61 (s, 2H), 0.48 (s, 2H). 62 2-(1-Propenyl-4-(2-((1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8- Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1470
 MS: 610 1 H NMR (400 MHz, MeOD) δ 7.58 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.30 (d, J = 5.5 Hz, 1H), 7.20 (d, J = 7.7 Hz, 2H), 7.15 (s, 1H), 6.73 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.73 (d, J = 10.4 Hz, 1H), 4.99 (d, J = 57.6 Hz, 2H), 4.16 – 4.01 (m, 3H), 3.97 (d, J = 10.2 Hz, 2H), 3.68 – 3.52 (m, 3H), 3.48 – 3.30 (m, 2H), 3.19 – 2.94 (m , 7H), 2.81 (s, 4H), 2.59 (dd, J = 30.3, 15.3 Hz, 2H), 2.51 (d, J = 12.7 Hz, 2H), 0.48 (d, J = 3.5 Hz, 2H), 0.41 (s, 2H). 63 2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(4-methylpiperazine-1-carbonyl)cyclopropyl)methoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1472
 MS:649 64 2-(1-Propenyl-4-(2-((1-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)cyclopropyl)methoxy)- 7-(8-Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1474
 MS: 637 1 H NMR (400 MHz, MeOD) δ 7.79 – 7.63 (m, 2H), 7.48 – 7.40 (m, 1H), 7.39 – 7.19 (m, 3H), 6.97 – 6.74 (m, 1H), 6.32 (d, J = 16.6 Hz, 1H), 5.86 (d, J = 10.5 Hz, 1H), 4.46 – 3.93 (m, 6H), 3.76 - 3.51 (m, 4H), 3.30 – 3.05 (m, 5H), 2.94 (s, 3H), 2.92 – 2.85 (m, 1H), 2.83 – 2.65 (m, 1H), 2.64 – 2.53 (m, 4H), 2.53 – 2.38 (m, 2H), 2.37 – 2.24 (m, 8H) ), 1.47 – 1.27 (m, 1H), 0.74 – 0.62 (m, 2H), 0.58 – 0.43 (m, 2H). 65 2-(1-Propenyl-4-(2-((1-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy) -7-(8-Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1476
 MS: 649 1 H NMR (400 MHz, MeOD) δ 7.78 – 7.62 (m, 2H), 7.48 – 7.40 (m, 1H), 7.38 – 7.21 (m, 3H), 6.96 – 6.76 (m, 1H), 6.32 (d, J = 16.5 Hz, 1H), 5.86 (d, J = 10.4 Hz, 1H), 4.43 – 4.02 (m, 6H), 3.86 – 3.64 (m, 2H), 3.61 – 3.41 (m, 2H), 3.30 – 3.05 (m, 5H), 2.94 (s, 3H), 2.91 – 2.86 (m, 1H), 2.81 – 2.72 (m, 2H), 2.70 – 2.43 (m, 4H), 2.25 (s, 6H), 2.12 – 1.93 (m, 1H), 1.85 – 1.69 (m, 1H), 1.41 – 1.25 (m, 2H), 0.74 – 0.62 (m, 2H), 0.57 – 0.48 (m, 2H). 66 2-(4-(2-((1-((4-Acetylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-propenylpiperazin-2-yl)acetonitrile
Figure 02_image1478
 MS: 663 1 H NMR (400 MHz, MeOD) δ 7.75 – 7.63 (m, 2H), 7.48 – 7.40 (m, 1H), 7.39 – 7.22 (m, 3H), 6.99 – 6.75 (m, 1H), 6.32 (d, J = 17.0 Hz, 1H), 5.86 (d, J = 10.3 Hz, 1H), 4.44 – 4.03 (m, 6H), 3.80 – 3.65 (m, 1H), 3.64 – 3.42 (m, 6H), 3.34 – 3.07 (m, 6H), 2.94 (s, 3H), 2.93 – 2.86 (m, 1H), 2.83 – 2.66 (m, 1H), 2.61 – 2.37 (m, 6H), 2.10 (s, 3H), 0.77 – 0.62 (m, 2H), 0.55 – 0.42 (m, 2H). 67 (S)-2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl) Methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1480
 MS: 606 1 H NMR (400 MHz, MeOD) δ 7.74 – 7.65 (m, 2H), 7.48 – 7.39 (m, 1H), 7.38 – 7.25 (m, 3H), 6.99 – 6.76 (m, 1H), 6.32 (d, 1H), 5.86 (d, 1H), 4.39 – 4.05 (m, 6H), 3.72 (t, 1H), 3.62 – 3.43 (m, 2H), 3.30 – 3.05 (m, 5H), 3.03 – 2.88 (m, 4H), 2.85 – 2.49 (m, 8H), 1.91 – 1.68 (m, 4H), 0.74 – 0.48 (m, 4H).

實施例68

Figure 02_image1482
Example 68
Figure 02_image1482

步驟a：向中間體D3 (0.97 g, 1.55 mmol)的DCM(10 mL)溶液中加入TFA (3.5 mL)。反應體系於25℃攪拌反應1小時。反應結束，體系減壓濃縮。殘餘物溶於DCM(10 mL)。向溶液中加入DIEA (4.0 mL)、中間體E1 (803 mg, 7.72 mmol)和HATU (2.99 g, 7.86 mmol)，混合體系於25℃攪拌0.5小時。體系減壓濃縮，殘餘物以矽膠層析法(50-30% DCM in MeOH)純化得粗品。粗品以Pre-HPLC(柱子: Daisogel-C18-10um-100A; 流動相: [水 (20 mmol NH4 HCO3 )-ACN]; B%:30%-60%, 30 min)純化，得到類白色固體化合物68 (196 mg, 0.32 mmol, 20.78 % 產率)。MS: m/z 612 [M+H]+ 。1 H NMR (400 MHz, MeOD) δ 7.83 – 7.62 (m, 2H), 7.55 – 7.17 (m, 4H), 7.09 – 6.48 (m, 2H), 5.41 – 5.01 (m, 2H), 4.48 – 3.91 (m, 6H), 3.88 – 3.43 (m, 4H), 3.28 – 3.04 (m, 4H), 2.94 (s, 3H), 2.88 – 2.59 (m, 2H), 2.60 – 2.39 (m, 2H), 2.32 (s, 6H), 1.41 – 1.16 (m, 1H), 0.83 – 0.65 (m, 2H), 0.61 – 0.35 (m, 2H)。Step a: To a solution of Intermediate D3 (0.97 g, 1.55 mmol) in DCM (10 mL) was added TFA (3.5 mL). The reaction system was stirred at 25°C for 1 hour. After the reaction was completed, the system was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL). To the solution were added DIEA (4.0 mL), Intermediate E1 (803 mg, 7.72 mmol) and HATU (2.99 g, 7.86 mmol), and the mixed system was stirred at 25° C. for 0.5 hour. The system was concentrated under reduced pressure and the residue was purified by silica gel chromatography (50-30% DCM in MeOH) to give crude product. The crude product is Pre-HPLC (column: Daisogel-C18-10um-100A; mobile phase: [water (20 mmol NH 4 HCO 3) -ACN]; B%: 30% -60%, 30 min) to give an off-white Solid compound 68 (196 mg, 0.32 mmol, 20.78 % yield). MS: m/z 612 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.83 – 7.62 (m, 2H), 7.55 – 7.17 (m, 4H), 7.09 – 6.48 (m, 2H), 5.41 – 5.01 (m, 2H), 4.48 – 3.91 ( m, 6H), 3.88 – 3.43 (m, 4H), 3.28 – 3.04 (m, 4H), 2.94 (s, 3H), 2.88 – 2.59 (m, 2H), 2.60 – 2.39 (m, 2H), 2.32 ( s, 6H), 1.41 – 1.16 (m, 1H), 0.83 – 0.65 (m, 2H), 0.61 – 0.35 (m, 2H).

使用上述工藝或修改工藝，以相應的原料合成了以下化合物。 化合物 化學名稱 結構式 MS: (M+H)+ /1 HNMR 69       (E)-2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(4-羥基丁-2-烯醯基)哌嗪-2-基)乙腈

Figure 02_image1483
MS:6101 H NMR (400 MHz, MeOD) δ 7.74 – 7.65 (m, 2H), 7.48 – 7.39 (m, 1H), 7.38 – 7.25 (m, 3H), 6.99 – 6.76 (m, 1H), 6.32 (d, 1H), 5.86 (d, 1H), 4.39 – 4.05 (m, 6H), 3.72 (t, 1H), 3.62 – 3.43 (m, 2H), 3.30 – 3.05 (m, 5H), 3.03 – 2.88 (m, 4H), 2.85 – 2.49 (m, 8H), 1.91 – 1.68 (m, 4H), 0.74 – 0.48 (m, 4H). 70       (E)-2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(4-甲氧基丁-2-烯醯基)哌嗪-2-基)乙腈
Figure 02_image1485
 MS:6241 H NMR (400 MHz, MeOD) δ 7.83 – 7.66 (m, 2H), 7.50 – 7.43 (m, 1H), 7.41 – 7.33 (m, 2H), 7.32 – 7.25 (m, 1H), 6.99 – 6.83 (m, 1H), 6.82 – 6.60 (m, 1H), 5.15 – 4.98 (m, 1H), 4.66 – 4.50 (m, 1H), 4.49 – 4.28 (m, 2H), 4.26 – 4.02 (m, 2H), 3.91 – 3.79 (m, 2H), 3.64 – 3.20 (m, 10H), 3.17 – 2.64 (m, 15H), 1.07 – 0.80 (m, 4H). 71       2-(1-(2-氟丙烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-((4-甲基哌嗪-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1487
 MS:653 72       2-(1-(2-氟丙烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1489
 MS:6241 H NMR (400 MHz, MeOD) δ 7.58 (d,J = 8.0 Hz, 1H), 7.54 (d,J = 7.9 Hz, 1H), 7.35 – 7.26 (m, 1H), 7.20 (dd,J = 13.4, 5.8 Hz, 2H), 7.14 (d,J = 7.1 Hz, 1H), 6.70 (s, 1H), 6.19 (d,J = 16.8 Hz, 1H), 5.74 (s, 1H), 4.95 (s, 1H), 4.31 – 4.03 (m, 4H), 4.05 – 3.90 (m, 2H), 3.59 (m, 2H), 3.42 (dd,J = 15.2, 9.9 Hz, 2H), 3.17 – 2.92 (m, 4H), 2.79 (d,J = 10.8 Hz, 4H), 2.59 (d,J = 16.1 Hz, 6H), 1.73 (s, 4H), 0.58 (d,J = 2.4 Hz, 2H), 0.45 (s, 2H). 73       2-(4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1491
 MS:6101 H NMR (400 MHz, MeOD) δ 7.57 (dd,J = 16.3, 8.2 Hz, 2H), 7.36 – 7.27 (m, 1H), 7.18 (dt,J = 17.1, 7.2 Hz, 3H), 5.31 – 5.13 (m, 2H), 4.10 (d,J = 8.2 Hz, 3H), 4.08 – 3.90 (m, 6H), 3.70 – 3.52 (m, 2H), 3.43 (d,J = 7.4 Hz, 2H), 3.17 – 2.94 (m, 6H), 2.80 (s, 3H), 2.39 – 2.24 (m, 2H), 1.26 (dd,J = 6.9, 4.6 Hz, 2H), 1.19 (d,J = 3.1 Hz, 2H), 0.67 (s, 4H). 74       (E)-2-(1-(丁-2-烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1493
 MS:6201 H NMR (400 MHz, MeOD) δ 7.61 (d,J = 8.1 Hz, 1H), 7.57 (d,J = 8.0 Hz, 1H), 7.33 (dd,J = 13.4, 7.6 Hz, 1H), 7.23 (d,J = 7.7 Hz, 2H), 7.17 (s, 1H), 5.88 (td,J = 16.5, 6.4 Hz, 1H), 5.26 – 5.08 (m, 2H), 4.95 (d,J = 19.5 Hz, 1H), 4.51 (d,J = 30.8 Hz, 1H), 4.19 (s, 2H), 4.14 – 3.94 (m, 3H), 3.62 (t,J = 19.1 Hz, 2H), 3.51 – 3.31 (m, 2H), 3.13 (s, 4H), 2.83 (s, 3H), 2.78 (dd,J = 7.4, 3.6 Hz, 1H), 2.63 (d,J = 11.4 Hz, 7H), 1.76 (s, 4H), 1.22 (s, 2H), 0.61 (s, 2H), 0.48 (s, 2H). 75       2-(4-(2-((1-((3-(二甲基氨基)氮雜環丁烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1495
 MS:6531 H NMR (400 MHz, MeOD) δ 7.71 (d,J = 8.1 Hz, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.32 (d,J = 7.7 Hz, 2H), 7.27 (s, 1H), 5.43 – 5.26 (m, 2H), 4.20 (d,J = 9.3 Hz, 4H), 4.08 (s, 2H), 3.72 (s, 4H), 3.60 – 3.42 (m, 2H), 3.22 (d,J = 4.1 Hz, 4H), 3.10 (s, 3H), 3.05 – 2.97 (m, 2H), 2.92 (s, 3H), 2.70 (s, 3H), 2.14 (s, 6H), 0.64 (d,J = 3.0 Hz, 2H), 0.57 (s, 2H). 76       2-(4-(2-((1-((二乙基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1497
 MS:6261 H NMR (400 MHz, MeOD) δ 7.72 (dd,J = 16.7, 7.9 Hz, 2H), 7.50 – 7.43 (m, 1H), 7.41 – 7.26 (m, 3H), 5.48 – 5.30 (m, 2H), 4.43 – 4.09 (m, 6H), 3.75 (dd,J = 17.7, 13.9 Hz, 1H), 3.63 – 3.47 (m, 2H), 3.34 – 3.06 (m, 5H), 2.95 (s, 3H), 2.84 – 2.51 (m, 8H), 1.44 – 1.31 (m, 1H), 1.07 (t,J = 6.7 Hz, 6H), 0.76 – 0.64 (m, 2H), 0.61 – 0.49 (m, 2H). 77       (E)-2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(4-氟丁-2-烯醯基)哌嗪-2-基)乙腈
Figure 02_image1499
 MS:6121 H NMR (400 MHz, MeOD) δ 7.76 – 7.65 (m, 2H), 7.47 – 7.41 (m, 1H), 7.38 – 7.24 (m, 3H), 7.02 – 6.72 (m, 2H), 5.23 – 5.07 (m, 2H), 4.31 – 4.04 (m, 5H), 3.87 – 3.66 (m, 2H), 3.62 – 3.42 (m, 2H), 3.30 – 3.07 (m, 6H), 2.94 (s, 3H), 2.92 – 2.85 (m, 1H), 2.81 – 2.64 (m, 1H), 2.51 – 2.38 (m, 2H), 2.32 (s, 6H), 0.79 – 0.64 (m, 2H), 0.52 (s, 2H). 78       2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1501
 MS:5981 H NMR (400 MHz, MeOD) δ 7.82 – 7.64 (m, 2H), 7.49 – 7.40 (m, 1H), 7.39 – 7.24 (m, 3H), 5.46 – 5.24 (m, 2H), 4.45 – 4.00 (m, 6H), 3.79 – 3.66 (m, 1H), 3.63 – 3.44 (m, 2H), 3.32 – 3.02 (m, 5H), 2.94 (s, 3H), 2.85 – 2.64 (m, 2H), 2.63 – 2.45 (m, 2H), 2.38 (s, 6H), 1.44 – 1.27 (m, 1H), 0.83 – 0.66 (m, 2H), 0.62 – 0.46 (m, 2H). 79       2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1503
 MS:6181 H NMR (400 MHz, MeOD) δ 7.81 (d,J = 8.0 Hz, 1H), 7.67 (d,J = 8.0 Hz, 1H), 7.59 – 7.43 (m, 2H), 7.41 – 7.20 (m, 2H), 5.47 – 5.17 (m, 2H), 4.49 – 3.95 (m, 6H), 3.79 – 3.37 (m, 3H), 3.23 – 2.98 (m, 7H), 2.96 – 2.91 (m, 1H), 2.88 (s, 6H), 2.77 – 2.59 (m, 1H), 2.10 – 1.96 (m, 1H), 0.94 – 0.66 (m, 4H). 80       2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(2,3-二甲基氨基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1505
 MS:5621 H NMR (400 MHz, MeOD) δ 7.11 (t, 1H), 7.04 – 6.92 (m, 2H), 5.45 – 5.23 (m, 2H), 4.35 (d, 3H), 4.20 (d, 1H), 4.01 (d, 2H), 3.47 – 3.30 (m, 6H), 3.27 – 3.04 (m, 5H), 3.03 – 2.77 (m, 8H), 2.32 (s, 6H), 0.97 – 0.87 (m, 4H). 81       2-(4-(2-((1-((3,3-二氟吡咯烷-1-基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1507
 MS:6601 H NMR (400 MHz, MeOD) δ 7.71 (d, 1H), 7.67 (d, 1H), 7.47 – 7.40 (m, 1H), 7.37 – 7.24 (m, 3H), 5.45 – 5.27 (m, 2H), 4.41 – 4.05 (m, 6H), 3.84 – 3.42 (m, 4H), 3.33 – 3.04 (m, 5H), 3.02 – 2.87 (m, 6H), 2.84 – 2.47 (m, 5H), 2.30 – 2.14 (m, 2H), 0.71 – 0.42 (m, 4H). 82       (E)-2-(1-(丁-2-烯醯基)-4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(2,3-二甲基氨基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1509
 MS:5581 H NMR (400 MHz, MeOD) δ 7.09 (t, 1H), 7.02 – 6.88 (m, 3H), 5.25 (m, 2H), 4.31 – 4.14 (m, 4H), 3.95 (d, 2H), 3.33 – 3.07 (m, 6H), 3.07 – 2.84 (m, 7H), 2.70 (m, 6H), 2.31 (m, 6H), 1.96 (d, 2H), 0.87 – 0.82 (m, 2H), 0.74 – 0.70 (m, 2H). 83       (S)-2-(4-(2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1511
 MS:5981 H NMR (400 MHz, MeOD) δ 7.72 (d, 1H), 7.68 (d, 1H), 7.49 – 7.40 (m, 1H), 7.38 – 7.30 (m, 2H), 7.27 (d, 1H), 5.43 – 5.29 (m, 2H), 4.31 – 4.16 (m, 4H), 4.16 – 4.01 (m, 2H), 3.78 – 3.50 (m, 4H), 3.32 – 3.00 (m, 7H), 2.82 – 2.67 (m, 2H), 2.55 – 2.31 (m, 9H), 0.75 – 0.70 (m, 2H), 0.57 – 0.52 (m, 2H). 84       (S,E)-2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(4-氟丁-2-烯醯基)哌嗪-2-基)乙腈
Figure 02_image1513
 MS:632 Using the above procedure or a modified procedure, the following compounds were synthesized from the corresponding starting materials. compound Chemical Name Structural formula MS: (M+H) + / 1 HNMR 69 (E)-2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-hydroxybut-2-enyl)piperazin-2-yl)acetonitrile
Figure 02_image1483
 MS: 610 1 H NMR (400 MHz, MeOD) δ 7.74 – 7.65 (m, 2H), 7.48 – 7.39 (m, 1H), 7.38 – 7.25 (m, 3H), 6.99 – 6.76 (m, 1H), 6.32 (d, 1H), 5.86 (d, 1H), 4.39 – 4.05 (m, 6H), 3.72 (t, 1H), 3.62 – 3.43 (m, 2H), 3.30 – 3.05 (m, 5H), 3.03 – 2.88 (m, 4H), 2.85 – 2.49 (m, 8H), 1.91 – 1.68 (m, 4H), 0.74 – 0.48 (m, 4H). 70 (E)-2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-methoxybut-2-enyl)piperazin-2-yl)acetonitrile
Figure 02_image1485
 MS: 624 1 H NMR (400 MHz, MeOD) δ 7.83 – 7.66 (m, 2H), 7.50 – 7.43 (m, 1H), 7.41 – 7.33 (m, 2H), 7.32 – 7.25 (m, 1H), 6.99 – 6.83 (m, 1H), 6.82 – 6.60 (m, 1H), 5.15 – 4.98 (m, 1H), 4.66 – 4.50 (m, 1H), 4.49 – 4.28 (m, 2H), 4.26 – 4.02 (m, 2H), 3.91 – 3.79 (m, 2H), 3.64 – 3.20 (m, 10H), 3.17 – 2.64 (m, 15H), 1.07 – 0.80 (m, 4H). 71 2-(1-(2-Fluoropropenyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-((4-methylpiperazin-1-yl) Methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1487
 MS:653 72 2-(1-(2-Fluoropropenyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1489
 MS: 624 1 H NMR (400 MHz, MeOD) δ 7.58 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.35 – 7.26 (m, 1H), 7.20 (dd, J = 13.4, 5.8 Hz, 2H), 7.14 (d, J = 7.1 Hz, 1H), 6.70 (s, 1H), 6.19 (d, J = 16.8 Hz, 1H), 5.74 (s, 1H), 4.95 ( s, 1H), 4.31 – 4.03 (m, 4H), 4.05 – 3.90 (m, 2H), 3.59 (m, 2H), 3.42 (dd, J = 15.2, 9.9 Hz, 2H), 3.17 – 2.92 (m, 4H), 2.79 (d, J = 10.8 Hz, 4H), 2.59 (d, J = 16.1 Hz, 6H), 1.73 (s, 4H), 0.58 (d, J = 2.4 Hz, 2H), 0.45 (s, 2H). 73 2-(4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1491
 MS: 610 1 H NMR (400 MHz, MeOD) δ 7.57 (dd, J = 16.3, 8.2 Hz, 2H), 7.36 – 7.27 (m, 1H), 7.18 (dt, J = 17.1, 7.2 Hz, 3H), 5.31 – 5.13 (m, 2H), 4.10 (d, J = 8.2 Hz, 3H), 4.08 – 3.90 (m, 6H), 3.70 – 3.52 (m, 2H), 3.43 (d, J = 7.4 Hz, 2H) , 3.17 – 2.94 (m, 6H), 2.80 (s, 3H), 2.39 – 2.24 (m, 2H), 1.26 (dd, J = 6.9, 4.6 Hz, 2H), 1.19 (d, J = 3.1 Hz, 2H) ), 0.67 (s, 4H). 74 (E)-2-(1-(But-2-enyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl) yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1493
 MS: 620 1 H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 13.4, 7.6 Hz, 1H) , 7.23 (d, J = 7.7 Hz, 2H), 7.17 (s, 1H), 5.88 (td, J = 16.5, 6.4 Hz, 1H), 5.26 – 5.08 (m, 2H), 4.95 (d, J = 19.5 Hz, 1H), 4.51 (d, J = 30.8 Hz, 1H), 4.19 (s, 2H), 4.14 – 3.94 (m, 3H), 3.62 (t, J = 19.1 Hz, 2H), 3.51 – 3.31 (m , 2H), 3.13 (s, 4H), 2.83 (s, 3H), 2.78 (dd, J = 7.4, 3.6 Hz, 1H), 2.63 (d, J = 11.4 Hz, 7H), 1.76 (s, 4H) , 1.22 (s, 2H), 0.61 (s, 2H), 0.48 (s, 2H). 75 2-(4-(2-((1-((3-(dimethylamino)azetidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-methyl) naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoropropenyl)piperazin-2-yl ) acetonitrile
Figure 02_image1495
 MS: 653 1 H NMR (400 MHz, MeOD) δ 7.71 (d, J = 8.1 Hz, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.32 (d, J = 7.7 Hz, 2H) , 7.27 (s, 1H), 5.43 – 5.26 (m, 2H), 4.20 (d, J = 9.3 Hz, 4H), 4.08 (s, 2H), 3.72 (s, 4H), 3.60 – 3.42 (m, 2H ), 3.22 (d, J = 4.1 Hz, 4H), 3.10 (s, 3H), 3.05 – 2.97 (m, 2H), 2.92 (s, 3H), 2.70 (s, 3H), 2.14 (s, 6H) , 0.64 (d, J = 3.0 Hz, 2H), 0.57 (s, 2H). 76 2-(4-(2-((1-((diethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1497
 MS: 626 1 H NMR (400 MHz, MeOD) δ 7.72 (dd, J = 16.7, 7.9 Hz, 2H), 7.50 – 7.43 (m, 1H), 7.41 – 7.26 (m, 3H), 5.48 – 5.30 (m , 2H), 4.43 – 4.09 (m, 6H), 3.75 (dd, J = 17.7, 13.9 Hz, 1H), 3.63 – 3.47 (m, 2H), 3.34 – 3.06 (m, 5H), 2.95 (s, 3H) ), 2.84 – 2.51 (m, 8H), 1.44 – 1.31 (m, 1H), 1.07 (t, J = 6.7 Hz, 6H), 0.76 – 0.64 (m, 2H), 0.61 – 0.49 (m, 2H). 77 (E)-2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-fluorobut-2-enyl)piperazin-2-yl)acetonitrile
Figure 02_image1499
 MS: 612 1 H NMR (400 MHz, MeOD) δ 7.76 – 7.65 (m, 2H), 7.47 – 7.41 (m, 1H), 7.38 – 7.24 (m, 3H), 7.02 – 6.72 (m, 2H), 5.23 – 5.07 (m, 2H), 4.31 – 4.04 (m, 5H), 3.87 – 3.66 (m, 2H), 3.62 – 3.42 (m, 2H), 3.30 – 3.07 (m, 6H), 2.94 (s, 3H) , 2.92 – 2.85 (m, 1H), 2.81 – 2.64 (m, 1H), 2.51 – 2.38 (m, 2H), 2.32 (s, 6H), 0.79 – 0.64 (m, 2H), 0.52 (s, 2H) . 78 2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1501
 MS: 598 1 H NMR (400 MHz, MeOD) δ 7.82 – 7.64 (m, 2H), 7.49 – 7.40 (m, 1H), 7.39 – 7.24 (m, 3H), 5.46 – 5.24 (m, 2H), 4.45 – 4.00 (m, 6H), 3.79 – 3.66 (m, 1H), 3.63 – 3.44 (m, 2H), 3.32 – 3.02 (m, 5H), 2.94 (s, 3H), 2.85 – 2.64 (m, 2H) , 2.63 – 2.45 (m, 2H), 2.38 (s, 6H), 1.44 – 1.27 (m, 1H), 0.83 – 0.66 (m, 2H), 0.62 – 0.46 (m, 2H). 79 2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7, 8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1503
 MS: 618 1 H NMR (400 MHz, MeOD) δ 7.81 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.59 – 7.43 (m, 2H), 7.41 – 7.20 ( m, 2H), 5.47 – 5.17 (m, 2H), 4.49 – 3.95 (m, 6H), 3.79 – 3.37 (m, 3H), 3.23 – 2.98 (m, 7H), 2.96 – 2.91 (m, 1H), 2.88 (s, 6H), 2.77 – 2.59 (m, 1H), 2.10 – 1.96 (m, 1H), 0.94 – 0.66 (m, 4H). 80 2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(2,3-dimethylamino)-5,6,7, 8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1505
 MS: 562 1 H NMR (400 MHz, MeOD) δ 7.11 (t, 1H), 7.04 – 6.92 (m, 2H), 5.45 – 5.23 (m, 2H), 4.35 (d, 3H), 4.20 (d, 1H) ), 4.01 (d, 2H), 3.47 – 3.30 (m, 6H), 3.27 – 3.04 (m, 5H), 3.03 – 2.77 (m, 8H), 2.32 (s, 6H), 0.97 – 0.87 (m, 4H) ). 81 2-(4-(2-((1-((3,3-Difluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1507
 MS: 660 1 H NMR (400 MHz, MeOD) δ 7.71 (d, 1H), 7.67 (d, 1H), 7.47 – 7.40 (m, 1H), 7.37 – 7.24 (m, 3H), 5.45 – 5.27 (m , 2H), 4.41 – 4.05 (m, 6H), 3.84 – 3.42 (m, 4H), 3.33 – 3.04 (m, 5H), 3.02 – 2.87 (m, 6H), 2.84 – 2.47 (m, 5H), 2.30 – 2.14 (m, 2H), 0.71 – 0.42 (m, 4H). 82 (E)-2-(1-(But-2-enyl)-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-( 2,3-Dimethylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1509
 MS: 558 1 H NMR (400 MHz, MeOD) δ 7.09 (t, 1H), 7.02 – 6.88 (m, 3H), 5.25 (m, 2H), 4.31 – 4.14 (m, 4H), 3.95 (d, 2H) ), 3.33 – 3.07 (m, 6H), 3.07 – 2.84 (m, 7H), 2.70 (m, 6H), 2.31 (m, 6H), 1.96 (d, 2H), 0.87 – 0.82 (m, 2H), 0.74 – 0.70 (m, 2H). 83 (S)-2-(4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1511
 MS: 598 1 H NMR (400 MHz, MeOD) δ 7.72 (d, 1H), 7.68 (d, 1H), 7.49 – 7.40 (m, 1H), 7.38 – 7.30 (m, 2H), 7.27 (d, 1H) ), 5.43 – 5.29 (m, 2H), 4.31 – 4.16 (m, 4H), 4.16 – 4.01 (m, 2H), 3.78 – 3.50 (m, 4H), 3.32 – 3.00 (m, 7H), 2.82 – 2.67 (m, 2H), 2.55 – 2.31 (m, 9H), 0.75 – 0.70 (m, 2H), 0.57 – 0.52 (m, 2H). 84 (S,E)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-fluorobut-2-enyl)piperazin-2-yl)acetonitrile
Figure 02_image1513
 MS:632

實施例 85

Figure 02_image1515
Example 85
Figure 02_image1515

步驟a：將TFA (3 mL)加入到化合物85-1 (488 mg, 0.78 mmol)的DCM(10 mL)溶液中。混合體系於25℃攪拌3小時。體系以飽和碳酸氫鈉溶液調pH＞7，並以DCM(50 mL×2)萃取。有機相以無水硫酸鈉乾燥，過濾並減壓濃縮得到化合物85-2 (445 mg)。MS: m/z 526 [M+1]+ 。Step a: TFA (3 mL) was added to a solution of compound 85-1 (488 mg, 0.78 mmol) in DCM (10 mL). The mixed system was stirred at 25°C for 3 hours. The system was adjusted to pH>7 with saturated sodium bicarbonate solution and extracted with DCM (50 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 85-2 (445 mg). MS: m/z 526 [M+1] + .

步驟b：將HATU (247 mg,0.65 mmol)加入到化合物85-2 (194 mg, 0.37 mmol)和(2E)-4-溴-2-丁烯酸(79 mg, 0.48 mmol)的DCM(10 mL)溶液中。體系於室溫攪拌2小時。體系加入30 mL飽和食鹽水。體系以DCM(30mL×2)萃取。合併有機相，無水硫酸鈉乾燥，過濾並濃縮得到化合物85-3 (286 mg)。MS: m/z 672 and 674 [M+1]+ 。Step b: HATU (247 mg, 0.65 mmol) was added to compound 85-2 (194 mg, 0.37 mmol) and (2E)-4-bromo-2-butenoic acid (79 mg, 0.48 mmol) in DCM (10 mL) solution. The system was stirred at room temperature for 2 hours. 30 mL of saturated brine was added to the system. The system was extracted with DCM (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 85-3 (286 mg). MS: m/z 672 and 674 [M+1] + .

步驟c：化合物85-3 (286 mg, 0.43 mmol)、二甲胺(4 mol/L in THF, 2 mL)和DIEA (2 mL)溶於DMF (5 mL)，室溫攪拌1小時。體系加入水(50mL)。體系以EtOAc (30 mL×2)萃取。合併有機相，飽和食鹽水(50mL×2)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物以薄層色譜法和pre-HPLC純化得到化合物85 (34 mg)。MS: m/z 637 [M+1]+ 。Step c: Compound 85-3 (286 mg, 0.43 mmol), dimethylamine (4 mol/L in THF, 2 mL) and DIEA (2 mL) were dissolved in DMF (5 mL) and stirred at room temperature for 1 hour. Water (50 mL) was added to the system. The system was extracted with EtOAc (30 mL×2). The organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by thin layer chromatography and pre-HPLC to give compound 85 (34 mg). MS: m/z 637 [M+1] + .

使用上述步驟和相應的起始原料合併下列化合物。 化合物 化學名稱 結構式 MS: (M+H)+ /1 HNMR 86 (E)-2-(1-(4-(二甲基氨基)丁-2-烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈

Figure 02_image1517
MS:6631 H NMR (400 MHz, MeOD) δ 7.62 (d,J = 8.2 Hz, 1H), 7.58 (d,J = 7.8 Hz, 1H), 7.34 (dd,J = 13.5, 7.7 Hz, 1H), 7.23 (dd,J = 16.5, 8.7 Hz, 2H), 7.17 (d,J = 7.0 Hz, 1H), 6.83 – 6.70 (m, 1H), 6.61 (s, 1H), 4.33 – 4.08 (m, 4H), 4.02 (dd,J = 17.9, 10.3 Hz, 3H), 3.63 (t,J = 18.4 Hz, 2H), 3.43 (d,J = 15.5 Hz, 2H), 3.13 (s, 4H), 2.84 (s, 3H), 2.67 (d,J = 14.8 Hz, 7H), 2.23 (s, 6H), 1.78 (s, 3H), 1.22 (s, 4H), 0.63 (s, 2H), 0.50 (s, 2H). The following compounds were combined using the above procedure and the corresponding starting materials. compound Chemical Name Structural formula MS: (M+H) + / 1 HNMR 86 (E)-2-(1-(4-(Dimethylamino)but-2-enyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1- (pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl ) acetonitrile
Figure 02_image1517
 MS: 663 1 H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.34 (dd, J = 13.5, 7.7 Hz, 1H) , 7.23 (dd, J = 16.5, 8.7 Hz, 2H), 7.17 (d, J = 7.0 Hz, 1H), 6.83 – 6.70 (m, 1H), 6.61 (s, 1H), 4.33 – 4.08 (m, 4H) ), 4.02 (dd, J = 17.9, 10.3 Hz, 3H), 3.63 (t, J = 18.4 Hz, 2H), 3.43 (d, J = 15.5 Hz, 2H), 3.13 (s, 4H), 2.84 (s , 3H), 2.67 (d, J = 14.8 Hz, 7H), 2.23 (s, 6H), 1.78 (s, 3H), 1.22 (s, 4H), 0.63 (s, 2H), 0.50 (s, 2H) .

下面列表中的化合物87- 208是使用可商購的中間體，按照一般反應方案和示例性實施例中概述的方法製備的。 化合物 化學名稱 結構式 MS: (M+H)+ 87       (S)-2-(1-丙烯醯基-4-(7-(3-氟-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈

Figure 02_image1519
628 88       (S)-2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1521
 610 89       (S)-2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1523
 644 90       2-(1-丙烯醯基-4-(7-(5-氯-4-(三氟甲基)吡啶-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1525
 645 91       (S)-2-(1-丙烯醯基-4-(7-(5-氯-4-(三氟甲基)吡啶-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1527
 645 92       (S)-2-(1-(2-氟丙烯醯基)-4-(2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-7-(2-(三氟甲基)吡啶-3-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1529
 629 93       (S)-2-(1-(2-氟丙烯醯基)-4-(7-(8-甲基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1531
 624 94       2-(4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1533
 645 95       (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1535
 645 96       2-(1-丙烯醯基-4-(2-((1-((3,3-二氟吡咯烷-1-基)甲基)環丙基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1537
 660 97       2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(((S)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1539
 662 98       (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1541
 630 99       (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1543
 648 100    (S)-2-(1-丙烯醯基-4-(7-(3-甲基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1545
 610 101    (S)-2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1547
 630 102    2-((S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((1-((S)-3-氟吡咯烷-1-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1549
 614 103    2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(2,3-二氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1551
 596 104    (S)-2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(3-氯-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1553
 630 105    (S)-2-(4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(3-氯-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1555
 648 106    (S)-2-(4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1557
 630 107    (S)-2-(4-(2-((1-(氮雜環丁烷-1-基甲基)環丙基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1559
 610 108    (S)-2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-((1-(嗎福林甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1561
 622 109    (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-(嗎福林甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1563
 660 110    2-((S)-1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-(((1R,2S)-2-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1565
 600 111    2-((S)-4-(7-(8-氯萘-1-基)-2-(((1S,2R)-2-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1567
 618 112    2-((S)-1-((E)-丁-2-烯醯基)-4-(7-(8-氯萘-1-基)-2-(((1S,2S)-2-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1569
 614 113    2-((S)-4-(7-(8-氯萘-1-基)-2-(((1R,2R)-2-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-((E)-4-氟丁-2-烯醯基)哌嗪-2-基)乙腈
Figure 02_image1571
 632 114    2-((S)-4-(7-(8-氯萘-1-基)-2-(((1R,3S)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1573
 632 115    2-((S)-1-((E)-丁-2-烯醯基)-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(((1S,3R)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1575
 646 116    2-((S)-1-丙烯醯基-4-(2-(((1R,3R)-3-(二甲基氨基)環戊基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1577
 612 117    2-((S)-4-(7-(2,3-二氯苯基)-2-(((1S,3S)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-((E)-4-氟丁-2-烯醯基)哌嗪-2-基)乙腈
Figure 02_image1579
 630 118    2-((S)-1-丙烯醯基-4-(2-(((1R,3S)-3-(二甲基氨基)環戊基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1581
 612 119    2-((S)-1-丙烯醯基-4-(2-(((1R,3R)-3-(二甲基氨基)環戊基)甲氧基)-7-(4-(三氟甲基)吡啶-3-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1583
 599 120    2-((S)-4-(7-(5-氯-4-(三氟甲基)吡啶-3-基)-2-(((1S,3S)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1585
 651 121    2-((S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(((1S,3R)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1587
 632 122    2-((S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-(((1R,3R)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1589
 598 123    2-((S)-1-丙烯醯基-4-(2-(((1R,3R)-3-(二甲基氨基)環戊基)甲氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1591
 594 124    2-((S)-4-(7-(8-氯萘-1-基)-2-(((1S,3R)-3-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1593
 632 125    2-(4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((3-甲氧基吡咯烷-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1595
 692 126    (E)-2-(1-(丁-2-烯醯基)-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((4-甲基哌嗪-1-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1597
 687 127    2-(4-(2-((1-((6-氮雜螺[2.5]辛基-6-基)甲基)環丙基)甲氧基)-7-(3-氯-2-甲基苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-丙烯醯基哌嗪-2-基)乙腈
Figure 02_image1599
 630 128    2-(1-丙烯醯基-4-(2-((1-((4-甲氧基哌啶-1-基)甲基)環丙基)甲氧基)-7-(4-甲基-3,4-二氫-2H-苯并[b][1,4]惡嗪-5-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1601
 657 129    2-(1-丙烯醯基-4-(2-((1-((4-甲氧基哌啶-1-基)甲基)環丙基)甲氧基)-7-(1-甲基吲哚-7-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1603
 641 130    2-(4-(2-((1-(((1R,4R)-2-氧雜-5-氮雜雙環[2.2.1]庚烷-5-基)甲基)環丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-丙烯醯基哌嗪-2-基)乙腈
Figure 02_image1605
 654 131    2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(1-(2-(吡咯烷-1-基)乙基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1607
 644 132    2-(1-丙烯醯基-4-(7-(3-甲基-2-(三氟甲基)苯基)-2-(2-(1-(吡咯烷-1-基)環丙基)乙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1609
 624 133    2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(1-甲基哌啶-3-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1611
 658 134    (E)-2-(1-(丁-2-烯醯基)-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((6-甲基-2,6-二氮雜螺[3.3]庚烷-2-基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1613
 699 135    2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((二乙基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1615
 646 136    2-(1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1617
 626 137    (S)-2-(1-丙烯醯基-4-(7-(8-氯萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1619
 626 138    (S)-2-(1-丙烯醯基-4-(2-((1-(吡咯烷-1-基)環丙基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1621
 596 139    (S)-2-(1-丙烯醯基-4-(2-((1-(3,3-二氟吡咯烷-1-基)環丙基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1623
 646 140    2-((2S)-1-丙烯醯基-4-(7-(3-氟-2-(三氟甲基)苯基)-2-((1-(1-甲基吡咯烷-2-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1625
 628 141    2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-(4-羥基-1-甲基吡咯烷-2-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1627
 660 142    2-((2S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((2-甲基-1-(1-甲基吡咯烷-2-基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1629
 624 143    2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-(1-(吡咯烷-1-基甲基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1631
 596 144    2-(1-丙烯醯基-4-(2-(1-((二甲基氨基)甲基)環丙氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1633
 552 145    2-(1-丙烯醯基-4-(7-(8-甲基萘-1-基)-2-(1-(1-甲基吡咯烷-2-基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1635
 592 146    2-((2S)-4-(7-(8-氯萘-1-基)-2-(1-(4,4-二氟-1-甲基吡咯烷-2-基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1637
 666 147    2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-(1-(4-羥基-1-甲基吡咯烷-2-基)-2,2-二甲基環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1639
 606 148    2-((2S)-4-(7-(2-氯-3-氟苯基)-2-(1-(4-甲氧基-1-甲基吡咯烷-2-基)環丙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-((E)-4-(二甲基氨基)丁-2-烯醯基)哌嗪-2-基)乙腈
Figure 02_image1641
 667 149    2-((2S)-4-(2-(2-(二甲基氨基)環丙氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯醯基)哌嗪-2-基)乙腈
Figure 02_image1643
 556 150    2-((2S)-1-((E)-丁-2-烯醯基)-4-(2-(2-((二甲基氨基)甲基)環丙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1645
 580 151    2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環丙基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1647
 552 152    2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-氟苯基)-2-((2-((二甲基氨基)甲基)環丙基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1649
 568 153    2-((2S)-1-丙烯醯基-4-(2-((1R)-1-(2-(吡咯烷-1-基甲基)環丙基)乙氧基)-7-(鄰甲苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1651
 570 154    2-((2S)-1-丙烯醯基-4-(7-(3-氟-2-甲基苯基)-2-((1R)-1-(2-((1-甲基吡咯烷-2-基)甲基)環丙基)乙氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1653
 602 155    (S)-2-(1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-(1-(吡咯烷-1-基甲基)環丁氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1655
 610 156    2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(1-((1-甲基吡咯烷-2-基)甲基)環丁氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1657
 658 157    2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-(1-(1-甲基吡咯烷-2-基)環丁氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1659
 644 158    2-((2S)-1-丙烯醯基-4-(2-(2-(二甲基氨基)環丁氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1661
 570 159    (S)-2-(1-丙烯醯基-4-(2-(3-(乙基(甲基)氨基)環丁氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1663
 566 160    (S)-2-(1-丙烯醯基-4-(2-(3-(乙基(2-甲氧基乙基)氨基)環丁氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1665
 610 161    2-((2S)-1-丙烯醯基-4-(2-(3-(二甲基氨基)-2-(2-甲氧基乙基)環丁氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1667
 610 162    (S)-2-(1-丙烯醯基-4-(7-(萘-1-基)-2-(3-(吡咯烷-1-基)環丁氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1669
 578 163    (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(吡咯烷-1-基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1671
 576 164    2-((2S)-1-丙烯醯基-4-(2-((1-(1-甲基吡咯烷-3-基)環丁基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1673
 624 165    2-((2S)-1-丙烯醯基-4-(2-((1-(1-甲基吡咯烷-2-基)環丁基)甲氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1675
 624 166    2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環丁基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1677
 566 167    (S)-2-(1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((3-(二甲基氨基)環丁基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1679
 618 168    2-((S)-1-丙烯醯基-4-(2-((R)-1-(3-(二甲基氨基)環丁基)乙氧基)-7-(3-氟-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1681
 616 169    (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1683
 564 170    2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)-3-(三氟甲基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1685
 632 171    2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)-3-(三氟甲氧基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1687
 648 172    3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)環戊烷-1-腈
Figure 02_image1689
 589 173    乙基 3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)環戊烷-1-羧酸酯
Figure 02_image1691
 636 174    3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)-N,N-二甲基環戊烷-1-甲醯胺
Figure 02_image1693
 635 175    2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)-3-(吡咯烷-1-羧基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1695
 661 176    3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)-N-甲基環戊烷-1-甲醯胺
Figure 02_image1697
 621 177    2-((2S)-1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)-3-(噻唑-2-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1699
 647 178    (S)-2-(1-丙烯醯基-4-(7-(2,3-二氟苯基)-2-((1-(吡咯烷-1-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1701
 592 179    2-((2S)-1-丙烯醯基-4-(2-((1-(1-甲基吡咯烷-2-基)環戊基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1703
 620 180    2-((2S)-1-丙烯醯基-4-(7-(2-氯-3-氟苯基)-2-((2,2-二氟-1-(1-甲基吡咯烷-2-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1705
 658 181    2-((2S)-1-丙烯醯基-4-(7-(2-氯-3-氟苯基)-2-((1-(1-甲基吡咯烷-3-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1707
 622 182    2-((2S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((1-(1-異丙基吡咯烷-3-基)環戊基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1709
 666 183    (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-((二甲基氨基)甲基)環戊基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1711
 564 184    (S)-2-(1-丙烯醯基-4-(2-((1-(氮雜環丁烷-1-基甲基)環戊基)氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1713
 610 185    (S)-2-(1-丙烯醯基-4-(7-(3-氟-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環戊基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1715
 642 186    2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((1-((1-甲基吡咯烷-2-基)甲基)環戊基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1717
 672 187    2-((2S)-1-丙烯醯基-4-(2-((1-((4,4-二氟-1-甲基吡咯烷-2-基)甲基)環戊基)氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1719
 656 188    2-((2S)-1-丙烯醯基-4-(2-((1-(二氟(1-甲基吡咯烷-2-基)甲基)環戊基)氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1721
 688 189    2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1723
 598 190    2-((2S)-1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1725
 598 191    2-((2S)-1-丙烯醯基-4-(2-((3-(二甲基氨基)環戊基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1727
 612 192    2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環戊基)甲氧基)-7-(3-甲基-2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1729
 612 193    (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-((二甲基氨基)甲基)環己基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1731
 578 194    (S)-2-(1-丙烯醯基-4-(2-((1-(吡咯烷-1-基甲基)環己基)氧基)-7-(2-(三氟甲基)苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1733
 638 195    2-((2S)-1-丙烯醯基-4-(7-(2-氯-3-氟苯基)-2-((2-(二甲基氨基)環己基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1735
 582 196    2-((2S)-1-丙烯醯基-4-(7-(2,3-二氯苯基)-2-((2-(1-甲基氮雜環丁烷-2-基)環己基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1737
 624 197    2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((2-(二甲基氨基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1739
 646 198    2-((2S)-1-丙烯醯基-4-(2-((2-(二甲基氨基)環己基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1741
 594 199    (S)-2-(1-丙烯醯基-4-(7-(2-氯苯基)-2-((1-(二甲基氨基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1743
 578 200    (S)-2-(1-丙烯醯基-4-(7-(2,3-二氟苯基)-2-((1-((二甲基氨基)甲基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1745
 594 201    (S)-2-(1-丙烯醯基-4-(2-((4-(二甲基氨基)環己基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1747
 594 202    2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((2-(吡咯烷-1-基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1749
 672 203    2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((3-(二甲基氨基)環己基)甲氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1751
 646 204    2-((2S)-1-丙烯醯基-4-(7-(3-氯-2-(三氟甲基)苯基)-2-((3-(二甲基氨基)環己基)氧基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1753
 632 205    N-(3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)環戊基)乙醯胺
Figure 02_image1755
 621 206    3-(((4-((S)-4-丙烯醯基-3-(氰甲基)哌嗪-1-基)-7-(2-氯苯基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)-3-(二甲基氨基)-N,N-二甲基環戊烷-1-磺醯胺
Figure 02_image1757
 671          207    2-((2S)-1-丙烯醯基-4-(2-(((2-(二甲基氨基)環丁基)甲基)硫基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1759
 582 208    2-((2S)-1-丙烯醯基-4-(2-(((2-(二甲基氨基)環丁基)甲基)氨基)-7-(萘-1-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure 02_image1761
 565 Compounds 87-208 in the list below were prepared using commercially available intermediates following the methods outlined in the general reaction schemes and illustrative examples. compound Chemical Name Structural formula MS: (M+H) + 87 (S)-2-(1-Propenyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl) )cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1519
 628 88 (S)-2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methan oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1521
 610 89 (S)-2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl) )cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1523
 644 90 2-(1-Propenyl-4-(7-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2-((1-(pyrrolidin-1-ylmethyl) Cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1525
 645 91 (S)-2-(1-Propenyl-4-(7-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2-((1-(pyrrolidine-1- ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1527
 645 92 (S)-2-(1-(2-Fluoropropenyl)-4-(2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-7-(2 -(Trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1529
 629 93 (S)-2-(1-(2-Fluoropropenyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl) )cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1531
 624 94 2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7, 8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1533
 645 95 (S)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1535
 645 96 2-(1-Propenyl-4-(2-((1-((3,3-difluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-7-(3- Methyl-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1537
 660 97 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(((S)-3-fluoropyrrolidine-1 -yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1539
 662 98 (S)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1541
 630 99 (S)-2-(4-(7-(8-Chloro-7-fluoronaphthalen-1-yl)-2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1543
 648 100 (S)-2-(1-Propenyl-4-(7-(3-methyl-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-yl) Cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1545
 610 101 (S)-2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-yl)cycle) Propyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1547
 630 102 2-((S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((1-((S)-3-fluoropyrrolidin-1-yl) Cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1549
 614 103 2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(2,3-dichlorobenzene yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1551
 596 104 (S)-2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(3-chloro -2-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1553
 630 105 (S)-2-(4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(3-chloro-2-(trifluoro) Methyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoropropenyl)piperazin-2-yl) Acetonitrile
Figure 02_image1555
 648 106 (S)-2-(4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-chloronaphthalen-1-yl) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1557
 630 107 (S)-2-(4-(2-((1-(azetidin-1-ylmethyl)cyclopropyl)methoxy)-7-(8-methylnaphthalen-1-yl )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1559
 610 108 (S)-2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(mfolinmethyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1561
 622 109 (S)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-(Mofolinmethyl)cyclopropyl)methoxy)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1563
 660 110 2-((S)-1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((1R,2S)-2-(dimethylamino)cyclobutyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1565
 600 111 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((1S,2R)-2-(dimethylamino)cyclobutyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1567
 618 112 2-((S)-1-((E)-But-2-enyl)-4-(7-(8-chloronaphthalen-1-yl)-2-(((1S,2S)-2 -(Dimethylamino)cyclobutyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1569
 614 113 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((1R,2R)-2-(dimethylamino)cyclobutyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enyl)piperazin-2-yl ) acetonitrile
Figure 02_image1571
 632 114 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((1R,3S)-3-(dimethylamino)cyclopentyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1573
 632 115 2-((S)-1-((E)-But-2-enyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((( 1S,3R)-3-(dimethylamino)cyclopentyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine- 2-yl)acetonitrile
Figure 02_image1575
 646 116 2-((S)-1-Propenyl-4-(2-(((1R,3R)-3-(dimethylamino)cyclopentyl)methoxy)-7-(3-methyl) -2-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1577
 612 117 2-((S)-4-(7-(2,3-Dichlorophenyl)-2-(((1S,3S)-3-(dimethylamino)cyclopentyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enyl)piperazin-2-yl ) acetonitrile
Figure 02_image1579
 630 118 2-((S)-1-Propenyl-4-(2-(((1R,3S)-3-(dimethylamino)cyclopentyl)methoxy)-7-(3-methyl -2-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1581
 612 119 2-((S)-1-Propenyl-4-(2-(((1R,3R)-3-(dimethylamino)cyclopentyl)methoxy)-7-(4-(tris) Fluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1583
 599 120 2-((S)-4-(7-(5-Chloro-4-(trifluoromethyl)pyridin-3-yl)-2-(((1S,3S)-3-(dimethylamino) Cyclopentyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoropropenyl)piperazine-2- base) acetonitrile
Figure 02_image1585
 651 121 2-((S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,3R)-3-(dimethyl) ylamino)cyclopentyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1587
 632 122 2-((S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-(((1R,3R)-3-(dimethylamino)cyclopentyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1589
 598 123 2-((S)-1-Propenyl-4-(2-(((1R,3R)-3-(dimethylamino)cyclopentyl)methoxy)-7-(8-methyl) Naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1591
 594 124 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((1S,3R)-3-(dimethylamino)cyclopentyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1593
 632 125 2-(4-(7-(3-Chloro-2-(trifluoromethyl)phenyl)-2-((1-((3-methoxypyrrolidin-1-yl)methyl)cyclopropane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoropropenyl)piperazin-2-yl) Acetonitrile
Figure 02_image1595
 692 126 (E)-2-(1-(But-2-enyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((4 -Methylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine- 2-yl)acetonitrile
Figure 02_image1597
 687 127 2-(4-(2-((1-((6-Azaspiro[2.5]octyl-6-yl)methyl)cyclopropyl)methoxy)-7-(3-chloro-2- Methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-acryloylpiperazin-2-yl)acetonitrile
Figure 02_image1599
 630 128 2-(1-Propenyl-4-(2-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-7-(4-methyl) yl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine- 4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1601
 657 129 2-(1-Propenyl-4-(2-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-7-(1-methyl) ylindol-7-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1603
 641 130 2-(4-(2-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methane oxy)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-propenylpiperazine -2-yl)acetonitrile
Figure 02_image1605
 654 131 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(1-(2-(pyrrolidin-1-yl)ethyl) Cyclopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1607
 644 132 2-(1-Propenyl-4-(7-(3-methyl-2-(trifluoromethyl)phenyl)-2-(2-(1-(pyrrolidin-1-yl)cyclopropane) yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1609
 624 133 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(1-methylpiperidin-3-yl)cycle Propyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1611
 658 134 (E)-2-(1-(But-2-enyl)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((6 -Methyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1613
 699 135 2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((diethylamino)methyl)cyclopropyl) )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1615
 646 136 2-(1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1617
 626 137 (S)-2-(1-Propenyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methan oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1619
 626 138 (S)-2-(1-Propenyl-4-(2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)-7-(2-(trifluoromethyl) Phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1621
 596 139 (S)-2-(1-Propenyl-4-(2-((1-(3,3-difluoropyrrolidin-1-yl)cyclopropyl)methoxy)-7-(3- Methyl-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1623
 646 140 2-((2S)-1-Propenyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-((1-(1-methylpyrrolidine-2 -yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1625
 628 141 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-(4-hydroxy-1-methyl) Pyrrolidin-2-yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1627
 660 142 2-((2S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((2-methyl-1-(1-methylpyrrolidine-2- yl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1629
 624 143 2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropoxy)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1631
 596 144 2-(1-Propenyl-4-(2-(1-((dimethylamino)methyl)cyclopropoxy)-7-(naphthalen-1-yl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1633
 552 145 2-(1-Propenyl-4-(7-(8-methylnaphthalen-1-yl)-2-(1-(1-methylpyrrolidin-2-yl)cyclopropoxy)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1635
 592 146 2-((2S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(1-(4,4-difluoro-1-methylpyrrolidin-2-yl)cyclopropoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1637
 666 147 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-(1-(4-hydroxy-1-methylpyrrolidin-2-yl)-2, 2-Dimethylcyclopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1639
 606 148 2-((2S)-4-(7-(2-Chloro-3-fluorophenyl)-2-(1-(4-methoxy-1-methylpyrrolidin-2-yl)cyclopropoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-(dimethylamino)but-2-enyl yl)piperazin-2-yl)acetonitrile
Figure 02_image1641
 667 149 2-((2S)-4-(2-(2-(dimethylamino)cyclopropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure 02_image1643
 556 150 2-((2S)-1-((E)-But-2-enyl)-4-(2-(2-((dimethylamino)methyl)cyclopropoxy)-7-( 8-Methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1645
 580 151 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclopropyl)methoxy)-7-(naphthalen-1-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1647
 552 152 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-fluorophenyl)-2-((2-((dimethylamino)methyl)cyclopropyl) Methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1649
 568 153 2-((2S)-1-Propenyl-4-(2-((1R)-1-(2-(pyrrolidin-1-ylmethyl)cyclopropyl)ethoxy)-7-( o-Tolyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1651
 570 154 2-((2S)-1-Propenyl-4-(7-(3-fluoro-2-methylphenyl)-2-((1R)-1-(2-((1-methylpyrrole Alk-2-yl)methyl)cyclopropyl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl) Acetonitrile
Figure 02_image1653
 602 155 (S)-2-(1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-(1-(pyrrolidin-1-ylmethyl)cyclobutoxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1655
 610 156 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(1-((1-methylpyrrolidine-2 -yl)methyl)cyclobutoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1657
 658 157 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(1-(1-methylpyrrolidine-2- yl)cyclobutoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1659
 644 158 2-((2S)-1-Propenyl-4-(2-(2-(dimethylamino)cyclobutoxy)-7-(2-(trifluoromethyl)phenyl)-5, 6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1661
 570 159 (S)-2-(1-Propenyl-4-(2-(3-(ethyl(methyl)amino)cyclobutoxy)-7-(naphthalen-1-yl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1663
 566 160 (S)-2-(1-Propenyl-4-(2-(3-(ethyl(2-methoxyethyl)amino)cyclobutoxy)-7-(naphthalen-1-yl) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1665
 610 161 2-((2S)-1-Propenyl-4-(2-(3-(dimethylamino)-2-(2-methoxyethyl)cyclobutoxy)-7-(naphthalene- 1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1667
 610 162 (S)-2-(1-Propenyl-4-(7-(naphthalen-1-yl)-2-(3-(pyrrolidin-1-yl)cyclobutoxy)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1669
 578 163 (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(pyrrolidin-1-yl)cyclobutyl)methoxy)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1671
 576 164 2-((2S)-1-Propenyl-4-(2-((1-(1-methylpyrrolidin-3-yl)cyclobutyl)methoxy)-7-(2-(tri Fluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1673
 624 165 2-((2S)-1-Propenyl-4-(2-((1-(1-methylpyrrolidin-2-yl)cyclobutyl)methoxy)-7-(2-(tri Fluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1675
 624 166 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclobutyl)methoxy)-7-(naphthalen-1-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1677
 566 167 (S)-2-(1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((3-(dimethylamino)cyclobutyl) )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1679
 618 168 2-((S)-1-Propenyl-4-(2-((R)-1-(3-(dimethylamino)cyclobutyl)ethoxy)-7-(3-fluoro- 2-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1681
 616 169 (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)cyclopentyl)methoxy)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1683
 564 170 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)-3-(trifluoromethyl)cyclopentyl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1685
 632 171 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)-3-(trifluoromethoxy)cyclopentane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1687
 648 172 3-(((4-((S)-4-Propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)cyclopentane-1-carbonitrile
Figure 02_image1689
 589 173 Ethyl 3-(((4-((S)-4-propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)cyclopentane-1-carboxylate
Figure 02_image1691
 636 174 3-(((4-((S)-4-Propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)-N,N-dimethylcyclopentane-1-carboxamide
Figure 02_image1693
 635 175 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)-3-(pyrrolidine-1-carboxy) ring Amyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1695
 661 176 3-(((4-((S)-4-Propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)-N-methylcyclopentane-1-carboxamide
Figure 02_image1697
 621 177 2-((2S)-1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)-3-(thiazol-2-yl)cyclopentane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1699
 647 178 (S)-2-(1-Propenyl-4-(7-(2,3-difluorophenyl)-2-((1-(pyrrolidin-1-yl)cyclopentyl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1701
 592 179 2-((2S)-1-Propenyl-4-(2-((1-(1-methylpyrrolidin-2-yl)cyclopentyl)methoxy)-7-(naphthalene-1- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1703
 620 180 2-((2S)-1-Propenyl-4-(7-(2-chloro-3-fluorophenyl)-2-((2,2-difluoro-1-(1-methylpyrrolidine) -2-yl)cyclopentyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1705
 658 181 2-((2S)-1-Propenyl-4-(7-(2-chloro-3-fluorophenyl)-2-((1-(1-methylpyrrolidin-3-yl)cyclopentan yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1707
 622 182 2-((2S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((1-(1-isopropylpyrrolidin-3-yl)cyclopentane yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1709
 666 183 (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-((dimethylamino)methyl)cyclopentyl)oxy)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1711
 564 184 (S)-2-(1-Propenyl-4-(2-((1-(azetidin-1-ylmethyl)cyclopentyl)oxy)-7-(2-(tri Fluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1713
 610 185 (S)-2-(1-Propenyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl) )cyclopentyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1715
 642 186 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((1-methylpyrrolidine- 2-yl)methyl)cyclopentyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1717
 672 187 2-((2S)-1-Propenyl-4-(2-((1-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)cyclopentyl)oxy yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1719
 656 188 2-((2S)-1-Propenyl-4-(2-((1-(difluoro(1-methylpyrrolidin-2-yl)methyl)cyclopentyl)oxy)-7- (3-Methyl-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl) Acetonitrile
Figure 02_image1721
 688 189 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)oxy)-7-(3-methyl-2-(trifluoromethyl) yl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1723
 598 190 2-((2S)-1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)oxy)-7-(3-methyl-2-(trifluoromethyl) yl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1725
 598 191 2-((2S)-1-Propenyl-4-(2-((3-(dimethylamino)cyclopentyl)methoxy)-7-(3-methyl-2-(trifluoro) Methyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1727
 612 192 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclopentyl)methoxy)-7-(3-methyl-2-(trifluoro) Methyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1729
 612 193 (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-((dimethylamino)methyl)cyclohexyl)oxy)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1731
 578 194 (S)-2-(1-Propenyl-4-(2-((1-(pyrrolidin-1-ylmethyl)cyclohexyl)oxy)-7-(2-(trifluoromethyl) Phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1733
 638 195 2-((2S)-1-Propenyl-4-(7-(2-chloro-3-fluorophenyl)-2-((2-(dimethylamino)cyclohexyl)oxy)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1735
 582 196 2-((2S)-1-Propenyl-4-(7-(2,3-dichlorophenyl)-2-((2-(1-methylazetidin-2-yl) Cyclohexyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1737
 624 197 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((2-(dimethylamino)cyclohexyl) Methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1739
 646 198 2-((2S)-1-Propenyl-4-(2-((2-(dimethylamino)cyclohexyl)methoxy)-7-(naphthalen-1-yl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1741
 594 199 (S)-2-(1-Propenyl-4-(7-(2-chlorophenyl)-2-((1-(dimethylamino)cyclohexyl)methoxy)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1743
 578 200 (S)-2-(1-Propenyl-4-(7-(2,3-difluorophenyl)-2-((1-((dimethylamino)methyl)cyclohexyl)methoxy yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1745
 594 201 (S)-2-(1-Propenyl-4-(2-((4-(dimethylamino)cyclohexyl)methoxy)-7-(naphthalen-1-yl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1747
 594 202 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((2-(pyrrolidin-1-yl)cycle) Hexyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1749
 672 203 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((3-(dimethylamino)cyclohexyl) Methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1751
 646 204 2-((2S)-1-Propenyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-((3-(dimethylamino)cyclohexyl) oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1753
 632 205 N-(3-(((4-((S)-4-propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)cyclopentyl)acetamide
Figure 02_image1755
 621 206 3-(((4-((S)-4-Propenyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-chlorophenyl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-(dimethylamino)-N,N-dimethylcyclopentane-1-sulfonamide
Figure 02_image1757
 671 207 2-((2S)-1-Propenyl-4-(2-(((2-(dimethylamino)cyclobutyl)methyl)sulfanyl)-7-(naphthalen-1-yl)- 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1759
 582 208 2-((2S)-1-Propenyl-4-(2-(((2-(dimethylamino)cyclobutyl)methyl)amino)-7-(naphthalen-1-yl)-5 ,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
Figure 02_image1761
 565

藥理實驗Pharmacological experiments

1. SOS1催化的鳥苷酸交換實驗 先將HIS-KRAS (G12C, aa 2-185, Sino biological)用EDTA 緩衝液(20 mM HEPES, pH 7.4, 50 mM NaCl, 10 mM EDTA, 0.01%(v/v) Tween-20)稀釋至5 μM，25 °C條件下預處理30分鐘。後用測定緩衝液（25 mM HEPES, pH 7.4, 120 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.01% (v/v) Tween 20, 0.1% (w/v) BSA)將EDTA預處理過的HIS-KRAS（G12C）稀釋至12 nM並與120 nM GDP和6HIS-Tb cryptate Gold(Cisbio)在25 °C條件下孵育60分鐘，製備GDP-KRAS（G12C）。將GDP-KRAS（G12C）與稀釋好的化合物在384孔板中預孵育1小時後，加入SOS1 ExD(Flag tag, aa 564-1049)和BODIPY™ FL GTP (Invitrogen)起始交換反應（反應體系： 3 nM HIS-KRAS(G12C), 2 μM SOS1 ExD, 80 nM BODIPY™ FL GTP, 21 ng/mL MAb Anti 6HIS-Tb cryptate Gold），置於25°C反應4小時。使用Tecan Spark酶標儀測定TR-FRET信號，檢測參數設置如下：F486 激發波長 340 (35) nm, 吸收波長 486 (10) nm, 延遲時間 100 μs, 整合時間 200 μs; F515: 激發波長340 (35) nm, 吸收波長 515(10) nm, 延遲時間100 μs, 整合時間 200 μs. 計算每個孔的TR-FRET比值，TR-FRET ratio = （F515信號/F486信號）*10000。擬合標準曲線（4-parameter logistic model）並計算IC50 值，所得結果如下表1所示。1. SOS1-catalyzed guanylate exchange experiment HIS-KRAS (G12C, aa 2-185, Sino biological) was first treated with EDTA buffer (20 mM HEPES, pH 7.4, 50 mM NaCl, 10 mM EDTA, 0.01% (v /v) Tween-20) diluted to 5 μM and pretreated at 25 °C for 30 minutes. EDTA-pretreated with assay buffer (25 mM HEPES, pH 7.4, 120 mM NaCl, 5 mM MgCl, 1 mM DTT, 0.01% (v/v) Tween 20, 0.1% (w/v) BSA) GDP-KRAS (G12C) was prepared by diluting HIS-KRAS (G12C) to 12 nM and incubating with 120 nM GDP and 6HIS-Tb cryptate Gold (Cisbio) for 60 min at 25 °C. After pre-incubating GDP-KRAS (G12C) with diluted compounds in a 384-well plate for 1 hour, SOS1 ExD (Flag tag, aa 564-1049) and BODIPY™ FL GTP (Invitrogen) were added to initiate the exchange reaction (reaction system). : 3 nM HIS-KRAS(G12C), 2 μM SOS1 ExD, 80 nM BODIPY™ FL GTP, 21 ng/mL MAb Anti 6HIS-Tb cryptate Gold) at 25°C for 4 hours. The TR-FRET signal was measured using a Tecan Spark microplate reader. The detection parameters were set as follows: F486 excitation wavelength 340 (35) nm, absorption wavelength 486 (10) nm, delay time 100 μs, integration time 200 μs; F515: excitation wavelength 340 ( 35) nm, absorption wavelength 515(10) nm, delay time 100 μs, integration time 200 μs. Calculate the TR-FRET ratio of each well, TR-FRET ratio = (F515 signal/F486 signal)*10000. Fitting standard curve (4-parameter logistic model) 50, and calculates values IC, results are shown in Table 1 below.

2. 細胞內磷酸化ERK1/2（THR202/TYR204）蛋白水平檢測（HTRF） NCI-H358（KRAS G12C 突變）細胞培養條件：RPMI1640培養基（Gibco）+10% FBS（Gibco）。NCI-H358 以40,000個細胞/孔的密度接種至96孔細胞培養板內，並放置在細胞培養箱內（37℃，5% CO2 ）孵育過夜。第二天，將96孔細胞培養板內的培養液移除，並加入含梯度稀釋待測化合物的新鮮培養液（RPMI 1640+ 0.1% FBS），細胞培養板放置在細胞培養箱內（37℃，5% CO2 ）孵育2小時。將96孔細胞培養板內的培養液移除，每孔加入50 μL 的1× 細胞裂解液 (Cisbio)，將細胞培養板放置在微孔板恒溫孵育器內，25℃震盪孵育45分鐘。吸取2.5 μL/孔 HTRF® 預先混合的抗體 (Cisbio 64AERPEH)加入至384孔板 (Greiner)，吸取10 μL 細胞裂解液轉移至預先加入抗體的孔內，然後將384孔板放置在微孔板恒溫孵育器內，25℃孵育4小時。最後將384孔板Tecan Spark酶標儀中讀取HTRF值。擬合標準曲線（4-parameter logistic model）並計算IC50 值，所得結果如下表1所示。2. Intracellular phosphorylated ERK1/2 (THR202/TYR204) protein level detection (HTRF) NCI-H358 (KRAS G12C mutation) cell culture conditions: RPMI1640 medium (Gibco) + 10% FBS (Gibco). NCI-H358 was seeded into a 96-well cell culture plate at a density of 40,000 cells/well and incubated overnight in a cell incubator (37°C, 5% CO 2 ). The next day, the culture medium in the 96-well cell culture plate was removed, and fresh culture medium (RPMI 1640 + 0.1% FBS) containing the compound to be tested was added, and the cell culture plate was placed in a cell culture incubator (37°C). , 5% CO 2 ) for 2 hours. The culture medium in the 96-well cell culture plate was removed, 50 μL of 1× cell lysate (Cisbio) was added to each well, the cell culture plate was placed in a microplate incubator, and incubated at 25°C with shaking for 45 minutes. Pipette 2.5 μL/well of HTRF ® pre-mixed antibody (Cisbio 64AERPEH) into a 384-well plate (Greiner), pipette 10 μL of cell lysate and transfer it to the pre-added antibody well, then place the 384-well plate in a microplate thermostat Incubator at 25°C for 4 hours. Finally, the HTRF value was read in the 384-well plate Tecan Spark microplate reader. Fitting standard curve (4-parameter logistic model) 50, and calculates values IC, results are shown in Table 1 below.

3. 細胞增殖抑制實驗 NCI-H358（KRAS G12C 突變）細胞培養條件：RPMI1640培養基（Gibco）+10%FBS（Gibco）。NCI-H358 以3,000個細胞/孔（100μL/孔）的密度接種至96孔細胞培養板內，並放置在細胞培養箱內（37℃，5% CO2 ）孵育過夜。第二天，並加入用新鮮培養基梯度稀釋的待測化合物，再將細胞培養板放置在細胞培養箱內（37℃，5% CO2 ）孵育6天。將96孔細胞培養板內的培養液移除，每孔加入100 μL 新鮮培養基配製的1× CCK-8 (MCE)，將細胞培養板放置在細胞培養箱中孵育1.5-2小時。用Tecan Spark酶標儀讀取OD450值。擬合標準曲線（4-parameter logistic model）並計算IC50 值，所得結果如下表1所示。 表1 化合物 SOS1催化的鳥苷酸交換實驗 KRAS G12C IC50 , nM p-ERK IC50 , nM （NCI-H358） NCI-H358 增殖抑制 IC50 , nM 1 - 3201 - 2 ＞500 - - 3 12.08 452.9 408 4 18.91 97.7 93.27 5 19.59 330.2 173.6 6 178.5 591.9 579.5 7 - - - 8 407.6 769.4 3469 9 - 1152 888.3 10 1735 720 940.3 11 - 9861 - 12 176.2 518.1 644.6 13 683.8 1213 - 14 54.15 234.4 216.6 15 333.4 876.5 497.1 16 - 7056 - 17 83.6 312.2 299.3 18 428.2 879 506.7 19 371.9 748.5 - 20 19.4 127 101.7 21 - ＞1000 - 22 10.74 96.61 65.18 23 9.448 111.6 66.85 24 20.05 237.0 93.59 25 30.15 266.8 164.5 26 33.65 231.4 153.5 27 84.55 565.6 310.1 28 24.05 - 138.0 29 - ＞1000 - 30 - - - 31 - - - 32 - - 696.5 33 - 302.3 652.4 34 15.87 54.55 78.56 35 17.92 85.35 105.8 36 - - - 37 6.748 81.58 85.53 38 5.242 66.03 60.25 39 7.282 79.57 103.8 40 23.78 - 360.2 41 13.47 149.3 178.8 42 5.242 63.56 118.5 43 5.045 71.83 134.8 44 33.24 220.4 741.9 45 13.32 216.4 590.1 46 2.573 14.72 26.9 47 1.158 23.69 26.44 48 3.309 65.98 94.93 49 3.124 38.35 64.2 50 8.658 83.83 202.4 51 3.282 77.12 99.89 52 484.8 ＞500 - 53 174.3 ＞500 - 54 82.82 ＞500 ＞1000 55 ＞500 - - 56 3.186 38.23 22.42 57 28.06 296.5 522.2 58 1.47 44.34 36.92 59 1.105 57.25 61.87 60 - 7124 - 61 1.438 16.21 25.05 62 2.339 43.03 66.94 63 30.86 533.2 860.7 64 1.689 123.7 74.52 65 1.462 87.81 32.84 66 1.457 13.57 25.11 67 1.84 22.4 20.4 68 1.603 69.25 51.49 69 2.734 157.0 77.56 70 3.412 172.3 195.1 71 7.573 505.1 369.3 72 11.84 214.8 378.5 73 16.96 962.7 883.1 74 66.77 ＞500 1520 75 7.267 405.1 235.2 76 11.69 353.7 420.9 77 1.238 59.26 29.03 78 8.359 207.6 207.5 79 6.026 439 239.1 80 284.6 ＞500 - 81 ＞500 - - 82 211.2 ＞500 - 83 3.901 190.4 116.3 84 1.577 80.19 24.3 85 2.86 152.8 132.4 86 ＞500 130.7 102.7 3. Cell proliferation inhibition experiment NCI-H358 (KRAS G12C mutation) cell culture conditions: RPMI1640 medium (Gibco) + 10% FBS (Gibco). NCI-H358 was seeded into a 96-well cell culture plate at a density of 3,000 cells/well (100 μL/well) and incubated overnight in a cell culture incubator (37°C, 5% CO 2 ). The next day, the compound to be tested was added in a gradient dilution with fresh medium, and the cell culture plate was placed in a cell culture incubator (37°C, 5% CO 2 ) for 6 days. Remove the culture medium in the 96-well cell culture plate, add 100 μL of 1× CCK-8 (MCE) prepared in fresh medium to each well, and place the cell culture plate in a cell culture incubator for 1.5-2 hours. OD450 values were read with a Tecan Spark microplate reader. Fitting standard curve (4-parameter logistic model) 50, and calculates values IC, results are shown in Table 1 below. Table 1 compound SOS1-catalyzed guanylate exchange assay KRAS G12C IC 50 , nM p-ERK IC 50, nM ( NCI-H358) NCI-H358 Proliferation inhibition IC 50 , nM 1 - 3201 - 2 ＞500 - - 3 12.08 452.9 408 4 18.91 97.7 93.27 5 19.59 330.2 173.6 6 178.5 591.9 579.5 7 - - - 8 407.6 769.4 3469 9 - 1152 888.3 10 1735 720 940.3 11 - 9861 - 12 176.2 518.1 644.6 13 683.8 1213 - 14 54.15 234.4 216.6 15 333.4 876.5 497.1 16 - 7056 - 17 83.6 312.2 299.3 18 428.2 879 506.7 19 371.9 748.5 - 20 19.4 127 101.7 twenty one - >1000 - twenty two 10.74 96.61 65.18 twenty three 9.448 111.6 66.85 twenty four 20.05 237.0 93.59 25 30.15 266.8 164.5 26 33.65 231.4 153.5 27 84.55 565.6 310.1 28 24.05 - 138.0 29 - >1000 - 30 - - - 31 - - - 32 - - 696.5 33 - 302.3 652.4 34 15.87 54.55 78.56 35 17.92 85.35 105.8 36 - - - 37 6.748 81.58 85.53 38 5.242 66.03 60.25 39 7.282 79.57 103.8 40 23.78 - 360.2 41 13.47 149.3 178.8 42 5.242 63.56 118.5 43 5.045 71.83 134.8 44 33.24 220.4 741.9 45 13.32 216.4 590.1 46 2.573 14.72 26.9 47 1.158 23.69 26.44 48 3.309 65.98 94.93 49 3.124 38.35 64.2 50 8.658 83.83 202.4 51 3.282 77.12 99.89 52 484.8 ＞500 - 53 174.3 ＞500 - 54 82.82 ＞500 >1000 55 ＞500 - - 56 3.186 38.23 22.42 57 28.06 296.5 522.2 58 1.47 44.34 36.92 59 1.105 57.25 61.87 60 - 7124 - 61 1.438 16.21 25.05 62 2.339 43.03 66.94 63 30.86 533.2 860.7 64 1.689 123.7 74.52 65 1.462 87.81 32.84 66 1.457 13.57 25.11 67 1.84 22.4 20.4 68 1.603 69.25 51.49 69 2.734 157.0 77.56 70 3.412 172.3 195.1 71 7.573 505.1 369.3 72 11.84 214.8 378.5 73 16.96 962.7 883.1 74 66.77 ＞500 1520 75 7.267 405.1 235.2 76 11.69 353.7 420.9 77 1.238 59.26 29.03 78 8.359 207.6 207.5 79 6.026 439 239.1 80 284.6 ＞500 - 81 ＞500 - - 82 211.2 ＞500 - 83 3.901 190.4 116.3 84 1.577 80.19 24.3 85 2.86 152.8 132.4 86 ＞500 130.7 102.7

4. NCI-H1373異種移植腫瘤模型藥效實驗 每只實驗小鼠（BALB/c裸鼠，雌性，6-8周）於右側背部皮下接種5*106 個NCI-H1373細胞（PBS：基質膠，體積比1:1）。定期觀察腫瘤生長情況。腫瘤體積計算公式為V = (L * w 2) / 2，L和w分別腫瘤的長徑和短徑。待腫瘤生長至平均瘤體積為150-200mm3 時，根據腫瘤體積大小和小鼠體重隨機分組給藥(n=6/組)。每週測量兩次腫瘤體積和小鼠體重。計算化合物的腫瘤抑制效果：TGI% = (1- (Vt-Vt0 )/(Vc-Vc0 ))*100%，Vc和Vt分別為實驗結束時對照組和給藥組的平均瘤體積，Vc0和Vt0分別為開始給藥時對照組和給藥組的平均瘤體積。其中化合物56、化合物68、化合物83、MRTX849以及溶劑對照組的TGI%如表2所示，腫瘤體積隨細胞接種後的天數的變化如圖1所示，小鼠體重隨細胞接種後的天數的變化如圖2所示。化合物67、MRTX849以及溶劑對照組的TGI%如表3所示，腫瘤體積隨細胞接種後的天數的變化如圖3所示，小鼠體重隨細胞接種後的天數的變化如圖4所示。MRTX849的結構如下所示：

Figure 02_image1763
表2 組別 開始給藥時腫瘤體積, mm3 實驗結束時腫瘤體積 (第22天), mm3 TGI % 溶劑對照組 191 1914 - MRTX 849, 10 mg/kg, QD 191 553 79.0 化合物56, 10 mg/kg, BID 191 148 102.5 化合物68, 10 mg/kg, BID 191 490 82.6 化合物83 10 mg/kg, BID 191 374 89.4 表3 組別 開始給藥時腫瘤體積, mm3 實驗結束時腫瘤體積 (第22天), mm3 TGI % 溶劑對照組 188 1413 - MRTX 849, 10 mg/kg, QD 188 355 86.3 化合物67, 10 mg/kg, QD 188 114 106.1 由上表2、表3及圖1-圖4可以看出本發明具有良好的抑制腫瘤增長的活性，並且具有良好的安全性。4. Efficacy test of NCI-H1373 xenograft tumor model Each experimental mouse (BALB/c nude mouse, female, 6-8 weeks) was subcutaneously inoculated with 5*10 6 NCI-H1373 cells (PBS: Matrigel) on the right back. , volume ratio 1:1). Regular observation of tumor growth. The tumor volume was calculated as V = (L * w 2) / 2, where L and w were the long and short diameters of the tumor, respectively. When the tumor grew to an average tumor volume of 150-200 mm 3 , the mice were randomly divided into groups and administered according to the tumor volume and the weight of the mice (n=6/group). Tumor volumes and mouse body weights were measured twice weekly. Calculate the tumor inhibitory effect of the compound: TGI% = (1-(Vt-Vt 0 )/(Vc-Vc 0 ))*100%, Vc and Vt are the average tumor volume of the control group and the drug-administered group at the end of the experiment, respectively, Vc0 and Vt0 were the mean tumor volumes of the control group and the administration group at the start of administration, respectively. Among them, the TGI% of compound 56, compound 68, compound 83, MRTX849 and the solvent control group are shown in Table 2. The change of tumor volume with the days after cell inoculation is shown in Figure 1. The weight of mice varies with the days after cell inoculation. The changes are shown in Figure 2. The TGI% of compound 67, MRTX849 and the solvent control group are shown in Table 3, the changes of tumor volume with the days after cell inoculation are shown in Figure 3, and the changes of mouse body weight with the days after cell inoculation are shown in Figure 4. The structure of the MRTX849 is as follows:
Figure 02_image1763
Table 2 group Tumor volume at start of dosing, mm 3 Tumor volume at the end of the experiment (day 22), mm 3 TGI % solvent control 191 1914 - MRTX 849, 10 mg/kg, QD 191 553 79.0 Compound 56, 10 mg/kg, BID 191 148 102.5 Compound 68, 10 mg/kg, BID 191 490 82.6 Compound 83 10 mg/kg, BID 191 374 89.4 table 3 group Tumor volume at start of dosing, mm 3 Tumor volume at the end of the experiment (day 22), mm 3 TGI % solvent control 188 1413 - MRTX 849, 10 mg/kg, QD 188 355 86.3 Compound 67, 10 mg/kg, QD 188 114 106.1 It can be seen from the above Table 2, Table 3 and Figures 1 to 4 that the present invention has good tumor growth inhibitory activity and good safety.

當理解，如果本發明引用了任何現有技術出版物，則應理解為：這樣的引用並不意味著承認該出版物是任何國家本領域公知常識的一部分。儘管為了清楚理解起見，本發明通過示例的方式對上述發明進行了詳細描述，但是對於本領域通常知識者顯而易見的是，將進行某些較小的改變和修改。因此，說明書和實施例不應解釋為限制本發明的範圍。It is understood that if the present disclosure refers to any prior art publication, it should be understood that such citation does not imply an admission that such publication is part of the common general knowledge in the field in any country. Although the foregoing invention has been described in detail by way of example for the sake of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications will be made. Therefore, the specification and examples should not be construed to limit the scope of the present invention.

無none

圖1為採用化合物56、化合物68、化合物83、MRTX849抑制腫瘤增長實驗中腫瘤體積隨細胞接種後的天數的變化圖。 圖2採用化合物56、化合物68、化合物83、MRTX849抑制腫瘤增長實驗中小鼠體重隨細胞接種後的天數的變化圖。 圖3為採用化合物67、MRTX849抑制腫瘤增長實驗中腫瘤體積隨細胞接種後的天數的變化圖。 圖4採用化合物67、MRTX849抑制腫瘤增長實驗中小鼠體重隨細胞接種後的天數的變化圖。Fig. 1 is a graph showing the change of tumor volume with the days after cell inoculation in the tumor growth inhibition experiment using compound 56, compound 68, compound 83 and MRTX849. FIG. 2 is a graph of changes in mouse body weight with days after cell inoculation in the tumor growth inhibition experiment using compound 56, compound 68, compound 83, and MRTX849. Figure 3 is a graph showing the change of tumor volume with the days after cell inoculation in the tumor growth inhibition experiment using compound 67 and MRTX849. Figure 4 is a graph of changes in mouse body weight with the days after cell inoculation in the tumor growth inhibition experiment using compound 67 and MRTX849.

Claims (30)

一種式(I)的化合物、其藥學上可接受的鹽或其立體異構體，
Figure 109126693-A0305-02-0139-1
 其中，每個L1在每次出現時獨立地選自不存在；每個R1在每次出現時獨立地選自苯基、萘基、5元雜芳基、6元雜芳基、9元雜芳基或10元雜芳基，每個雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個R1在每次出現時獨立地可選地被1、2或3個R12取代或不取代；每個R12在每次出現時獨立地選自鹵素、氧代、-C1-6烷基、-C1-6亞烷基-(鹵素)1-3、-CN、-OR8、-O-C1-6亞烷基-(鹵素)1-3、-SR8、-S-C1-6亞烷基-(鹵素)1-3、-NR8R9；每個R2在每次出現時獨立地選自鹵素、氧代、-C1-6烷基、-C1-6亞烷基-(鹵素)1-3、-OR8、-NR8R9；每個L3在每次出現時獨立地選自O； 每個環A是3元碳環，所述的
Figure 109126693-A0305-02-0139-2
和
Figure 109126693-A0305-02-0139-3
連接在所述環A的相同的碳原子上；每個R3是-NR8R9；每個L4在每次出現時獨立地選自不存在； 每個R4在每次出現時獨立地選自
Figure 109126693-A0305-02-0140-4
，每個R4在每次出現時獨立地可選地被1、2或3個R42取代或不取代；每個G1、G2在每次出現時獨立地選自N；每個n1、n2在每次出現時獨立地選自1、2或3；每個R41在每次出現時獨立地選自
Figure 109126693-A0305-02-0140-5
；每個Q在每次出現時獨立地選自C(=O)；
Figure 109126693-A0305-02-0140-42
選自
Figure 109126693-A0305-02-0140-43
；每個R4a、R4b和R4c在每次出現時獨立地選自氫、鹵素、-C1-6烷基、-C1-6亞烷基-(鹵素)1-3、-C1-6亞烷基-(OR8)1-3、-C1-6亞烷基-NR8R9；每個R42選自-C1-6亞烷基-CN；每個R5和R6在每次出現時獨立地選自氫、-C1-6烷基或氧代；每個R7在每次出現時獨立地選自鹵素、-C1-6烷基、-C1-6亞烷基-(鹵素)1-3、氧代、-OR8、-NR8R9、-C(=O)R8；每個R8和R9在每次出現時獨立地選自氫或-C1-6烷基；或R8和R9與它們共同連接的N原子一起形成3-10元雜環，所述的3-10元雜環可進一步包含1、2、3或4個選自N、O、S、S(=O)或S(=O)2的雜原子，且所述的3-10元雜環獨立地可選地被1、2、3、4、5或6個R10取代或不取代；每個R10在每次出現時獨立地選自鹵素、氧代、-C1-6烷基、-C1-6亞烷基-(鹵素)1-3、-OH、-OC1-6烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、-C(=O)C1-6烷基；r選自0、1、2或3；s選自0、1、2或3；p選自1； q選自1。 a compound of formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
Figure 109126693-A0305-02-0139-1
 wherein each L 1 at each occurrence is independently selected from absent; each R 1 at each occurrence is independently selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 9 A membered heteroaryl or a 10 membered heteroaryl, each heteroaryl independently at each occurrence contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S; each R 1 in each independently optionally substituted or unsubstituted at each occurrence with 1, 2 or 3 R 12 ; each R 12 at each occurrence is independently selected from halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , -CN, -OR 8 , -OC 1-6 alkylene-(halogen) 1-3 , -SR 8 , -SC 1-6 alkylene- (halogen) 1-3 , -NR 8 R 9 ; each R 2 at each occurrence is independently selected from halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen ) 1-3 , -OR 8 , -NR 8 R 9 ; each L 3 is independently selected from O at each occurrence; each ring A is a 3-membered carbocyclic ring, the
Figure 109126693-A0305-02-0139-2
and
Figure 109126693-A0305-02-0139-3
Attached to the same carbon atom of the A ring; each R 3 is -NR 8 R 9; each L 4 is independently at each occurrence selected from absent; each R 4 is independently at each occurrence chosen from
Figure 109126693-A0305-02-0140-4
Each R 4 at each occurrence is independently optionally substituted with 1, 2 or 3 R 42 substituted or unsubstituted; each G 1, G 2 at each occurrence is independently selected from N; each of n1 , n2 at each occurrence is independently selected from 1, 2 or 3; each R41 at each occurrence is independently selected from
Figure 109126693-A0305-02-0140-5
; each Q is independently selected at each occurrence from C(=O);
Figure 109126693-A0305-02-0140-42
selected from
Figure 109126693-A0305-02-0140-43
; each R 4a , R 4b and R 4c at each occurrence is independently selected from hydrogen, halogen, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , -C 1-6 alkylene-(OR 8 ) 1-3 , -C 1-6 alkylene-NR 8 R 9 ; each R 42 is selected from -C 1-6 alkylene-CN; each R 5 and R 6 is independently selected at each occurrence from hydrogen, -C 1-6 alkyl or oxo; each R 7 is independently selected at each occurrence from halogen, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , oxo, -OR 8 , -NR 8 R 9 , -C(=O)R 8 ; each R 8 and R 9 are independently at each occurrence Selected from hydrogen or -C 1-6 alkyl; or R 8 and R 9 together with the N atom to which they are connected together form a 3-10-membered heterocycle, and the 3-10-membered heterocycle may further comprise 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O) or S(=O) 2 , and the 3-10 membered heterocyclic ring is independently optionally replaced by 1, 2, 3, 4, 5 or 6 R 10 substituted or unsubstituted; each R 10 at each occurrence is independently selected from halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen ) 1-3 , -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(=O)C 1-6 alkyl; r is selected from 0, 1, 2 or 3; s is selected from 0, 1, 2 or 3; p is selected from 1; q is selected from 1. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R1在每次出現時獨立地選自苯基、萘基、吡啶基、吲哚基、吲唑基、吲哚嗪基、苯并噻唑、苯并異噻唑、喹唑啉、異喹唑啉或鄰苯二甲醯基，每個R1在每次出現時獨立地可選地被1、2、3或4個R12取代或不被取代。 A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 1 is independently at each occurrence selected from phenyl, naphthyl, pyridine group, indolyl, indazolyl, indolizinyl, benzothiazole, benzisothiazole, quinazoline, isoquinoline or quinazoline phthaloyl acyl, each R 1 independently at each occurrence Optionally substituted or unsubstituted with 1, 2, 3 or 4 R 12 . 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R1選自：
Figure 109126693-A0305-02-0141-6
 每個R1在每次出現時獨立地可選地被1、2、3或4個R12取代或不取代。 The compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 1 is selected from:
Figure 109126693-A0305-02-0141-6
 Each R 1 is independently at each occurrence, optionally, three or four R 12 substituted or unsubstituted. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R12在每次出現時獨立地選自鹵素、氧代、-C1-3烷基、-C1-3亞烷基-(鹵素)1-3、-CN、-OR8、-O-C1-3亞烷基-(鹵素)1-3、-SR8、-S-C1-3亞烷基-(鹵素)1-3、-NR8R9；每個R12中的R8和R9在每次出現時獨立地選自氫或-C1-3烷基。 A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 12 is independently selected at each occurrence from halogen, oxo, -C 1-3 alkyl, -C 1-3 alkylene-(halogen) 1-3 , -CN, -OR 8 , -OC 1-3 alkylene-(halogen) 1-3 , -SR 8 , - SC 1-3 alkylene-(halogen) 1-3 , -NR 8 R 9 ; R 8 and R 9 in each R 12 are at each occurrence independently selected from hydrogen or -C 1-3 alkyl . 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R12在每次出現時獨立地選自-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、-CH2F、-CHF2、-CF3、-CN、-OH、-OCH3、-OCH(CH3)2、-OCF3、-SH、-SCH3、-SCF3、-NH2、-NHCH3、-N(CH3)2。 A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 12 is independently selected at each occurrence from -F, -Cl, - Br, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CN, -OH, -OCH 3 , -OCH(CH 3 ) 2 , - OCF 3 , -SH, -SCH 3 , -SCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 . 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R1選自：
Figure 109126693-A0305-02-0142-7
Figure 109126693-A0305-02-0143-9
 The compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 1 is selected from:
Figure 109126693-A0305-02-0142-7
Figure 109126693-A0305-02-0143-9
 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R2在每次出現時獨立地選自-F、-Cl、-Br、氧代、-C1-3烷基、-OR8、-NR8R9、；每個R2中的R8和R9在每次出現時獨立地選自氫或-C1-3烷基。 Said compound of formula requested item 1 (I) according to its pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 2 is independently at each occurrence selected from -F, -Cl, - Br, oxo, -C 1-3 alkyl, -OR 8 , -NR 8 R 9 ,; R 8 and R 9 in each R 2 are at each occurrence independently selected from hydrogen or -C 1- 3 alkyl. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R2在每次出現時獨立地選自-F、-Cl、-Br、氧代、甲基、乙基、丙基、異丙基、-OH、-OCH3、-OCH2CH3、-NH2、-NHCH3、-N(CH3)2。 Said compound of formula requested item 1 (I) according to its pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 2 is independently at each occurrence selected from -F, -Cl, - br, oxo, methyl, ethyl, propyl, isopropyl, -OH, -OCH 3, -OCH 2 CH 3, -NH 2, -NHCH 3, -N (CH 3) 2. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R3在每次出現時獨立地選自-NR8R9；每個R3中的R8和R9在每次出現時獨立地選自氫、甲基、乙基、丙基或異丙基；或R3中的R8和R9與它們共同連接的N原子一起形成3-6元雜環，所述的3-6元雜環可進一步包含1選自N的雜原子，且所述的3-6元雜環獨立地可選地被1、2、3、4、5或6個R10取代或不被取代。 The compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 3 is independently selected at each occurrence from -NR 8 R 9 ; each R 8 and R 9 in each R 3 are independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, or isopropyl; or the N to which R 8 and R 9 in R 3 are attached together The atoms together form a 3-6 membered heterocyclic ring, the 3-6 membered heterocyclic ring may further comprise 1 heteroatom selected from N, and the 3-6 membered heterocyclic ring can be independently optionally replaced by 1, 2, 3, 4, 5 or 6 R 10 are substituted or unsubstituted. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R3在每次出現時獨立地選自-NH2、-N(CH3)2、-N(CH3)(CH2CH3)、-N(CH2CH3)2、
Figure 109126693-A0305-02-0144-10
、
Figure 109126693-A0305-02-0144-11
或
Figure 109126693-A0305-02-0144-12
；每個R3獨立地可選地被1、2、3、4、5或6個R10取代或不取代。 The compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 3 is independently selected at each occurrence from -NH 2 , -N( CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 ,
Figure 109126693-A0305-02-0144-10
,
Figure 109126693-A0305-02-0144-11
or
Figure 109126693-A0305-02-0144-12
; Each R 3 is independently optionally substituted 5 or 6 unsubstituted or substituted with R 10. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R3在每次出現時獨立地選自-NH2、-N(CH3)2、-N(CH3)(CH2CH3)、-N(CH2CH3)2、
Figure 109126693-A0305-02-0144-13
、
Figure 109126693-A0305-02-0144-14
、
Figure 109126693-A0305-02-0144-15
、
Figure 109126693-A0305-02-0144-16
、
Figure 109126693-A0305-02-0144-17
、
Figure 109126693-A0305-02-0144-22
、
Figure 109126693-A0305-02-0144-19
、
Figure 109126693-A0305-02-0144-21
；每個R3獨立地可選地被1、2、3、4、5或6個R10取代或不被取代；每個R10在每次出現時獨立地選自-F、-Cl、-Br、氧代、-C1-3烷基、-C1-3亞烷基-(鹵素)1-3、-OH、-OC1-3烷基、-NH2、-NHC1-3烷基、-N(C1-3烷基)2或-C(=O)C1-3烷基。 The compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 3 is independently selected at each occurrence from -NH 2 , -N( CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 ,
Figure 109126693-A0305-02-0144-13
,
Figure 109126693-A0305-02-0144-14
,
Figure 109126693-A0305-02-0144-15
,
Figure 109126693-A0305-02-0144-16
,
Figure 109126693-A0305-02-0144-17
,
Figure 109126693-A0305-02-0144-22
,
Figure 109126693-A0305-02-0144-19
,
Figure 109126693-A0305-02-0144-21
; each R 3 is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R 10 ; each R 10 is independently selected at each occurrence from -F, -Cl, -Br, oxo, -C 1-3 alkyl, -C 1-3 alkylene-(halogen) 1-3 , -OH, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 alkyl) 2 or -C(=O)C 1-3 alkyl. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R10在每次出現時獨立地選自-F、-Cl、甲基、乙基、 丙基、異丙基、-CH2F、-CHF2、-CF3、-OH、-OCH3、-OCH2CH3、-NH2、-NHCH3、-N(CH3)2、-C(=O)CH3。 The compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 10 is independently selected at each occurrence from -F, -Cl, methyl base, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 . 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R3選自：
Figure 109126693-A0305-02-0145-23
 Said compound of formula requested item 1 (I) according to its pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 3 is selected from:
Figure 109126693-A0305-02-0145-23
 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R5和R6在每次出現時獨立地選自氫、-C1-3烷基。 The compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 5 and R 6 are independently selected at each occurrence from hydrogen, -C 1-3 alkyl. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R5和R6在每次出現時獨立地選自氫、甲基、乙基、丙基、異丙基。 A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 5 and R 6 are independently selected at each occurrence from hydrogen, methyl , ethyl, propyl, isopropyl. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R7在每次出現時獨立地選自-F、-Cl、-Br、-C1-3烷基、-C1-3亞烷基-(鹵素)1-3、氧代、-OR8、-NR8R9或-C(=O)R8。 A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 7 is independently selected at each occurrence from -F, -Cl, - Br, -C 1-3 alkyl, -C 1-3 alkylene-(halogen) 1-3 , oxo, -OR 8 , -NR 8 R 9 or -C(=O)R 8 . 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R7在每次出現時獨立地選自-F、-Cl、-Br、甲基、乙基、丙基、異丙基。 A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 7 is independently selected at each occurrence from -F, -Cl, - Br, methyl, ethyl, propyl, isopropyl. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，
Figure 109126693-A0305-02-0145-24
選自：
Figure 109126693-A0305-02-0146-25
 The compound of formula (I), its pharmaceutically acceptable salt or its stereoisomer according to claim 1, wherein,
Figure 109126693-A0305-02-0145-24
Selected from:
Figure 109126693-A0305-02-0146-25
 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，
Figure 109126693-A0305-02-0146-27
選自：
Figure 109126693-A0305-02-0146-26
 The compound of formula (I), its pharmaceutically acceptable salt or its stereoisomer according to claim 1, wherein,
Figure 109126693-A0305-02-0146-27
Selected from:
Figure 109126693-A0305-02-0146-26
 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R4在每次出現時獨立地選自
Figure 109126693-A0305-02-0146-28
；每個R4在每次出現時獨立地可選地被1、2、3、4、5或6個R42取代或不被取代。 Said compound of formula requested item 1 (I) according to its pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 4 is independently selected at each occurrence
Figure 109126693-A0305-02-0146-28
; Each R 4 is independently optionally substituted 5 or 6 or R 42 substituent is not substituted at each occurrence. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R41在每次出現時獨立地選自
Figure 109126693-A0305-02-0146-29
；每個Q在每次出現時獨立地選自或C(=O)。 A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 41 at each occurrence is independently selected from
Figure 109126693-A0305-02-0146-29
; each Q is independently selected at each occurrence from or C (=O). 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R4a、R4b和R4c在每次出現時獨立地選自氫、-F、-CH2F、甲基、-CH2N(CH3)2。 A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 4a , R 4b and R 4c at each occurrence is independently selected from hydrogen , -F, -CH 2 F, methyl, -CH 2 N(CH 3 ) 2 . 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，R41選自
Figure 109126693-A0305-02-0146-30
。 The compound of formula (I), its pharmaceutically acceptable salt or its stereoisomer according to claim 1, wherein R 41 is selected from
Figure 109126693-A0305-02-0146-30
. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R42選自-F、-C1-3烷基、-C1-3亞烷基-(鹵素)1-3、-C1-3亞烷基-CN。 The compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 42 is selected from -F, -C 1-3 alkyl, -C 1 -3 alkylene-(halogen) 1-3 , -C 1-3 alkylene-CN. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R42選自-亞甲基-CN。 The compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R 42 is selected from -methylene-CN. 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，其中，每個R4獨立地選自：
Figure 109126693-A0305-02-0147-31
 Said compound of formula requested item 1 (I) according to its pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 4 is independently selected from:
Figure 109126693-A0305-02-0147-31
 根據請求項1所述的式(I)的化合物、其藥學上可接受的鹽或其立體異構體，所述的化合物選自：
Figure 109126693-A0305-02-0147-32
Figure 109126693-A0305-02-0148-33
Figure 109126693-A0305-02-0149-34
Figure 109126693-A0305-02-0150-35
Figure 109126693-A0305-02-0151-36
Figure 109126693-A0305-02-0152-38
Figure 109126693-A0305-02-0153-41
 According to the compound of formula (I), its pharmaceutically acceptable salt or its stereoisomer according to claim 1, the compound is selected from:
Figure 109126693-A0305-02-0147-32
Figure 109126693-A0305-02-0148-33
Figure 109126693-A0305-02-0149-34
Figure 109126693-A0305-02-0150-35
Figure 109126693-A0305-02-0151-36
Figure 109126693-A0305-02-0152-38
Figure 109126693-A0305-02-0153-41
 一種藥物組合物，其包括至少一種請求項1-27中任一項所述的式I的化合物、其藥學上可接受的鹽或其立體異構體，和至少一種藥學上可接受的賦形劑。 A pharmaceutical composition comprising at least one compound of formula I according to any one of claims 1-27, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient agent. 一種如請求項1-27中任一項所述的式I的化合物、其藥學上可接受的鹽或其立體異構體、或如請求項28所述的藥物組合物在製備治療與KRAS G12C突變蛋白相關的癌症的藥物中的應用。 A compound of formula I as described in any one of claims 1-27, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition as described in claim 28 in the preparation of treatment with KRAS G12C Drug application of mutant protein-related cancers. 根據請求項29所述的應用，其中，所述的癌症選自血液癌、胰腺癌、結腸癌、直腸癌、結直腸癌或肺癌；所述的血液癌選自急性髓性白血病或急性淋巴細胞白血病；所述的肺癌選自非小細胞肺癌或小細胞肺癌。 The application according to claim 29, wherein the cancer is selected from blood cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer or lung cancer; the blood cancer is selected from acute myeloid leukemia or acute lymphocyte Leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
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